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1 Form Approved Through 11/30/2010 OMB No Department of Health and Human Services Public Health Services Grant Application Do not exceed character length restrictions indicated. 1. TITLE OF PROJECT (Do not exceed 81 characters, including spaces and punctuation.) ALZHEIMERS DISEASE RESEARCH CENTER LEAVE BLANK FOR PHS USE ONLY. Type Activity Number Review Group Formerly Council/Board (Month, Year) Date Received 2. RESPONSE TO SPECIFIC REQUEST FOR APPLICATIONS OR PROGRAM ANNOUNCEMENT OR SOLICITATION NO YES (If Yes, state number and title) Number: RFA-AG Title: Alzheimer's Diease Research Center (P50) 3. PROGRAM DIRECTOR/PRINCIPAL INVESTIGATOR New Investigator No Yes 3a. NAME (Last, first, middle) 3b. DEGREE(S) 3h. era Commons User Name MORRIS, JOHN C. MD J_MORRIS 3c. POSITION TITLE PROFESSOR OF NEUROLOGY 3e. DEPARTMENT, SERVICE, LABORATORY, OR EQUIVALENT NEUROLOGY 3f. MAJOR SUBDIVISION SCHOOL OF MEDICINE 3d. MAILING ADDRESS (Street, city, state, zip code) MEMORY & AGING PROJECT 4488 FOREST PARK AVE. ST. LOUIS, MO g. TELEPHONE AND FAX (Area code, number and extension) ADDRESS: TEL: FAX: HUMAN SUBJECTS RESEARCH 4a. Research Exempt If Yes, Exemption No. No Yes No Yes 4b. Federal-Wide Assurance No. 4c. Clinical Trial 4d. NIH-defined Phase III Clinical Trial FWA No Yes No Yes 5. VERTEBRATE ANIMALS No Yes 5a. Animal Welfare Assurance No. A DATES OF PROPOSED PERIOD OF SUPPORT (month, day, year MM/DD/YY) 7. COSTS REQUESTED FOR INITIAL BUDGET PERIOD 8. COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT From Through 7a. Direct Costs ($) 7b. Total Costs ($) 8a. Direct Costs ($) 8b. Total Costs ($) 05/01/10 04/30/15 $1,746,817 $2,631,452 $9,241,629 $13,978, APPLICANT ORGANIZATION 10. TYPE OF ORGANIZATION Name WASHINGTON UNIVERSITY Public: Federal State Local Address 660 SOUTH EUCLID AVE. ST. LOUIS, MO Private: Private Nonprofit For-profit: General Small Business Woman-owned Socially and Economically Disadvantaged 11. ENTITY IDENTIFICATION NUMBER A1 DUNS NO Cong. District ADMINISTRATIVE OFFICIAL TO BE NOTIFIED IF AWARD IS MADE 13. OFFICIAL SIGNING FOR APPLICANT ORGANIZATION Name JOHN MICHNOWICZ Name JOHN MICHNOWICZ Title DIRECTOR OF GRANTS & CONTRACTS Title DIRECTOR OF GRANTS & CONTRACTS Address 660 SOUTH EUCLID AVE. ST. LOUIS, MO Address 660 SOUTH EUCLID AVE. ST. LOUIS, MO Tel: FAX: Tel: FAX: G&C@msnotes.wustl.edu G&C@msnotes.wustl.edu 14. APPLICANT ORGANIZATION CERTIFICATION AND ACCEPTANCE: I certify that the statements herein are true, complete and accurate to the best of my knowledge, and accept the obligation to comply with Public Health Services terms and conditions if a grant is awarded as a result of this application. I am aware that any false, fictitious, or fraudulent statements or claims may subject me to criminal, civil, or administrative penalties. SIGNATURE OF OFFICIAL NAMED IN 13. (In ink. Per signature not acceptable.) DATE PHS 398 (Rev. 11/07) Face Page Form Page 1 Page 1

2 PROJECT SUMMARY (See instructions): The Washington University Alzheimer s Disease Research Center (ADRC) initiates, fosters, and supports the performance of innovative, cutting-edge research on Alzheimer s disease (AD) and related topics with regard to the etiology, pathogenesis, diagnosis, treatment, and prevention of disease. We provide well-characterized research participants (persons with AD and age-matched controls), their clinical, psychometric, and imaging data, and their tissue (blood, DNA, CSF, autopsy material) to research projects. We also provide intellectual and financial support to scientists at Washington University, at other Alzheimer s Centers, and the research community nationally and internationally and engage in formal and informal collaborations, including multi-disciplinary/multi-center studies and the initiatives sponsored by the National Institute on Aging, the National Alzheimer Coordinating Center, and the National Cell Repository for Alzheimer s Disease. Historically, our Center has focused on the earliest stages of dementia to identify the initial clinical and pathologic changes that distinguish AD from normal aging. Our approach is balanced between clinicopathologic and basic science domains with emphasis on interdisciplinary efforts. We will continue our training of students, fellows and junior faculty in clinical and basic science research skills. We will continue to engage in outreach activities to transfer information on AD to lay and professional audiences. We have a commitment to underserved populations that are the focus of our African American and Rural Satellites and will continue activities that promote the inclusion of these populations in research. This competing renewal application includes six cores: A: Administration, B: Clinical, C: Data Management and Statistics, D: Neuropathology, E: Education and F: Genetics. There are two satellites: African American (Core B: Clinical) and Rural (Core E: Education). The ADRC resources contained in these Cores and Satellites will promote and advance AD-related research as represented by the Three projects in this application: Project 1. Novel protein biomarkers for Alzheimer s disease in cerebrospinal fluid; (Richard Perrin) 2. Changing tau protein levels and tau protein isoforms in mouse models of dementia; (Timothy Miller) 3. APOE metabolism in AD and controls; (Randall Bateman). RELEVANCE (See instructions): The ADRC offers an unparalleled number of integrated and innovative studies to examine the clinical, cognitive, imaging, biochemical, molecular and genetic abnormalities related to AD pathogenesis. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: Washington University DUNS: Street 1: 660 South Euclid Ave. Street 2: Campus Box 8111 City: St. Louis County: State: MO Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: 1 Additional Project/Performance Site Location Organizational Name: Washington University DUNS: Street 1: 660 South Euclid Ave Street 2: Campus Box 8111 City: St. Louis County: State: MO Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: 1 PHS 398 (Rev. 11/07) Form Page 2 Page 2

3 Core or Project Program Director/Principal Investigator (Last, First, Middle): Morris, John C. SENIOR/KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Program Director(s)/Principal Investigator(s). List all other senior/key personnel in alphabetical order, last name first. Name era Commons User Name Organization Role on Project John C. Morris J_MORRIS Washington University PI, Leader Core A & B Randall J. Bateman RANDALLBATEMAN Washington University Leader Project 3 Nigel J. Cairns Nigel_Cairns Washington University Leader Core D Hana N. Dawson dawso009 Duke University Investigator Prj. 2 James E. Galvin GALVINJ Washington University Leader Core E & Rural Alison M. Goate goatea Washington University Leader Core F David M. Holtzman HOLTZMAND Washington University Assoc. Director Timothy M. Miller TIMOTHYMILLER Washington University Leader Project 2 Richard J. Perrin rperrin Washington University Leader Project 1 Monique M. Williams Monique_Williams Washington University Leader Minority Satellite Chengjie Xiong XIONGCHENGJIE Washington University Leader Core C OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells No Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line PHS 398 (Rev. 11/07) Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Page 3

4 Overview Principal Investigator/Program Director (Last, First, Middle): Morris, John C. RESOURCES FACILITIES: Specify the facilities to be used for the conduct of the proposed research. Indicate the performance sites and describe capacities, pertinent capabilities, relative proximity, and extent of availability to the project. If research involving Select Agent(s) will occur at any performance site(s), the biocontainment resources available at each site should be described. Under Other, identify support services such as machine shop, electronics shop, and specify the extent to which they will be available to the project. Use continuation pages if necessary. Institutional Resources for the ADRC Washington University and the School of Medicine: Research at Washington University is funded from many sources, including the federal and state governments, corporations, foundations, nonprofit agencies, individuals, and the University itself. During fiscal 2008, $471 million was received in total research support. During the same time period, gifts and grants from private sources, including alumni, individuals, foundations, corporations and other organizations totaled $100 million from 10,000 entities. The School of Medicine received $346 million in grants from the National Institutes of Health during the federal fiscal year ending Sept. 30, 2008, making it the fourth-largest recipient of NIH dollars among the 123 U.S. medical schools. That money came in 715 separate grants. Washington University School of Medicine in St. Louis remains No. 3 among research-oriented medical schools, according to the latest edition of U.S. News & World Report's "America's Best Graduate Schools." Hospital Affiliate: The School is aided in its clinical, teaching, and research missions by close ties with its major teaching hospitals, Barnes-Jewish Hospital and St. Louis Children s Hospital on the medical center campus and by interactions with affiliated hospitals throughout the growing Barnes-Jewish-Christian network of both acute and chronic care facilities in Missouri and Illinois. Barnes-Jewish Hospital, a 1,251-bed patient care, teaching and research facility, is the largest hospital in Missouri. It provides clinical experience for medical students in all clinical departments except pediatrics. The medical staff is composed exclusively of Washington University full-time or voluntary medical school faculty physicians. With a premier reputation in patient care, medical education, research and community service, the hospital has been ranked among an elite group of the nation's best academic hospitals on the U.S. News & World Report Honor Roll since 1993, ranking #12 in the nation in It is the first adult hospital in Missouri to be awarded Magnet status, nursing's highest honor for clinical excellence. Its areas of expertise include cancer, cardiology, endocrinology, gastroenterology, geriatrics, gynecology, neurology, ophthalmology, orthopedic surgery, otolaryngology, pulmonary disease, rheumatology, transplantation and urology. Barnes-Jewish Hospital is a member of BJC HealthCare, a regional, nonprofit health care organization that provides community-based and academic health care services through 13 hospitals and more than 100 inpatient and ambulatory care sites throughout Missouri and southern Illinois. Washington University Medical Center: The 230-acre Washington University Medical Center, spread over portions of 12 city blocks, is located along the eastern edge of Forest Park in St. Louis. At the western boundary of the park is the 169-acre Danforth Campus of Washington University in St. Louis. The Medical Center consists of Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis Children s Hospital, Barnard Hospital, Siteman Cancer Center and the Central Institute for the Deaf. It is closely affiliated with the BJC Health System, including the Mallinckrodt Institute of Radiology, nationally recognized programs in Physical and Occupational Therapy and the Institute of Biomedical Computing. The 302,000-square-foot Southwest Tower houses the 52,000 squre-foot Charles F. Knight Emergency and Trauma Center on the street level; 28 new operating rooms opened in this facility in January 2005, and a new cardiothoracic intensive care unit will open later in the year. The School of Medicine occupies 75,000 square feet of research space in this building. The Southwest Tower and the 650,000-square-foot Center for Advanced Medicine complete the medical center's $350 million campus integration project, which began in These capital improvements, with the 11-story McDonnell Pediatric Research Building, have added more than 609,000 square feet to the School of Medicine. Most outpatient, diagnostic and testing services, as well as cancer services, are now located on the north side of the campus, and all high-intensity, complex surgical cases and related care are delivered on its south end. The eight-level Northwest Tower opened in fall of This 200,000-square-foot facility provides faculty office space atop the St. Louis Children's Hospital garage. In September 2005 construction was completed on the 110,000-square-foot Farrell Learning and Teaching Center at Scott and Euclid avenues. The six-story building houses all of the medical school's teaching spaces PHS 398 (Rev. 11/07) Page 4 Resources Format Page

5 Overview Principal Investigator/Program Director (Last, First, Middle): Morris, John C. and individual student study areas, as well as two lecture halls and a cafe. Superb physical facilities already included: 1) a seven-story biomedical library and communications center (completed in 1989) that together occupy 83,000 square feet, have a storage capacity of 420,000 volumes, and offer 3,000 journal titles; 2) the Eric P. Newman Education Center, completed in 1995, with 44,000 square feet of excellent meeting space and state-of-the-art audiovisual equipment to support symposia and conferences, large and small; and 3) a new addition to the Clinical Sciences Research Building. A final stage calls for additional improvements adding another 60,000 square feet. In the aggregate, the School of Medicine occupies more than 4.5 million gross square feet with 2.1 million gross square feet dedicated to research Aging Research: Washington University has a long history of involvement in aging research. Many of the University s early investigators in this field were instrumental in establishing the Gerontological Society of America, whose national headquarters were located next to the WUSM campus until the late 1960 s. In addition to this Center application, the Healthy Aging and Senile Dementia program project, the Antecedent Biomarkers for AD: the Adult Children Study and the Dominantly Inherited Alzheimer Network collaborative project, the University s commitment to clinical aging research is demonstrated by the very successful and longstanding training program in the psychology of aging, until recently headed by Dr. Martha Storandt, now directed by Dr. David Balota, and the establishment of the Washington University Center for Aging, John C. Morris, Director. ADRC Facilities and Resources: The Center administration and its clinical research office, the Memory and Aging Project, are located in ample space in the WUSM-owned medical office building located 2 blocks east of Barnes-Jewish Hospital (5 minute walk from the medical center main campus). The Center offices and clinical operations moved to this site in 1995 to occupy 3,745 square feet of space. In 1999, 1500 sq feet was renovated and added to provide four offices and a large conference room. In the last 3 years, an additional 580 square feet was added to house the Education Core and add office and testing space. This space is ideally suited for the Center and its research participants, with ample and convenient parking with handicapped access. The St. Louis Metrolink connects the main campus of Washington University with the School of Medicine (the two campus are on opposite borders of Forest Park in St. Louis). The Center staff are supported by 35 PCs (personal computers), 6 laptops, and 39 printers, so that all personnel have ready access to computer resources. All systems have Windows XP Pro OS with up-to-date patches and security updates. All system clients, servers, and gateways are protected with Symantec Anti-Virus, are behind a Cisco firewall and are backed up to a hard disc array with 210 GB of capacity. All PCs have Internet access and are networked to the University system via Ethernet. Our file/print/mail/web servers include: (ABRAXAS, 90GB), where (electronic mail), electronic group calendaring/messaging, FTP, and file services are available. RUSH, 72 GB serves as a file server and houses our anti-virus programs. ALZHEIMER, 36 GB is a web server but is also used for archiving seminal dementia articles. In addition, the Center has developed secure procedures and hardware to scan subject records and store them electronically to be viewed from desk top computers in the research clinicians offices. We have ready access to the Biostatistics Core and statistical services (data entry, analyses, data management & scheduling) available on the Biostatistics Core s servers (WUBIOS and WUBIOSAS), as well as both the School of Medicine Library (OVID, PUBMED) and the General Studies Olin Library (WORLDWINDOW). We have available a wide range of online search, abstract, and text services, such as MEDLINE (since 1966), Current Contents - Science Editions (since 1995), HealthSTAR (health services, technology and research administration since 1975), CINAHL (nursing & allied health journals since 1982), and biomedical journals in searchable and readable full text edition. Medical School Core Facilities: The School of Medicine has recently cataloged its core research facilities and is identifying what additional core facilities would enhance the research potential of its faculty. About half of the 69 core facilities identified are available to all faculty investigators. The remainder have more restricted access but could but accessed if resources permit. These core facilities are grouped in the following categories: Morphology, Imaging and Spectroscopy, DNA Sequencing/Genetic Analysis, Transgenic Support, Protein/Lipid Analysis, Cells and Tissue Culture, Animal Studies/Clinical Studies, Biostatistics, and Other Facilities. Morphology, Imaging and Spectroscopy - Cardiovascular Magnetic Resonance Laboratory, Confocal Microscope Facility, Electron Microscope Facility (B), Fluorescence Correlation Spectroscopy/Confocal PHS 398 (Rev. 11/07) Page 5 Resources Format Page

6 Overview Principal Investigator/Program Director (Last, First, Middle): Morris, John C. Imaging, High Throughput Screening Core, Chemical Genetics and sirna Facilities, Molecular Microbiology Imaging Facility, Research Animal Diagnostic Laboratory, Research Center for Auditory and Vestibular Studies, Research Histopathology Core Research Animal Diagnostic Laboratory, Bakewell NeuroImaging Laboratory, Digestive Diseases Research Core Center - Morphology Core, Histology & Microscopy Core Facility, Immunopathology Core for Vision Research, Electron Microscope Facility (A) DNA Sequencing/Genetic Analysis - Protein and Nucleic Acid Chemistry Laboratories, DNA Sequencing. DNA Synthesis. Mass Spectrometry. Protein Sequencing, Sequencing Core, Automated Sequencing. Taqman Analysis, SNP Genotyping Core, SNP Research Facility, Speed Congenic Facility, Rheumatic Diseases Core Center, Molecular Biology Core for Vision Research, Molecular Core Lab (Siteman Cancer Center), Multiplexed Gene Analysis Core (Siteman Cancer Center) Transgenic Support - Embryonic Stem Cell Core (Cancer Center), Mouse Genetics Core, Speed Congenic Facility, Rheumatic Diseases Core Center, Transgenic Vectors Core, Microinjection Core - Pathology Department, Molecular Biology Core for Vision Transgenic and ES cell Injection, Transgene/ES cell Microinjections, Transgenic and ES Injection Protein/Lipid Analysis - Bioorganic Chemistry Analytical Core, Mass Spectrometry Facility - Dept. of Medicine, Mass Spectrometry Research Resource, Protein and Nucleic Acid Chemistry Laboratories, Chemistry Core, Chemistry Core, Pharmacology Core Laboratory in the Cancer Center Cells and Tissue Culture - Flow Cytometry - Molecular Biology Core for Vision Research, Flow Cytometry Center. High Speed Cell Sorter Core (Siteman Cancer Center), Hybridoma Center, Protein and Nucleic Acid Chemistry Laboratories, Tissue Culture Support Center, Cancer Center Tissue Procurement Core, Islet Isolation Core, Media Preparation Facility, Organ Culture Core (Renal), Tissue Culture Core (Medicine) Animal Studies/Clinical Studies - Animal Behavior Core, Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Magnetic Resonance Laboratory Center for Clinical Studies (CCS), Core Laboratory for Clinical Studies, Division of Comparative Medicine Educational Services, Division of Nuclear Medicine, Hereditary Cancer Core, Research Center for Auditory and Vestibular Studies Research Imaging Center (Mallinckrodt Inst of Radiology, Veterinary Surgical Services, Animal Facility (Radiology), Clinical Trials Core (Siteman Cancer Center) DRTC Core RIA lab, General Clinical Research Center (GCRC) Washington University, Mouse Cardiovascular Phenotyping Core, NNICU PET Research Facility, Pharmacology Core Laboratory in the Cancer Center, Small Animal Cancer Imaging Core (Siteman Cancer Center). Biostatistics - Biostatistics Core (Siteman Cancer Ctr), Department of Medicine Biostatistics Consulting Center, Division of Biostatistics, Biostatistics Core (Ophthalmology), Department-Specific Biostatistical/Epidemiological Facilities, MIR-Biostatistics, Wubios, A Computing Resource Genomics/Proteomics/Lipidomics - Core Lab for Clinical Studies, High Throughput Screening Core, Chemical Genetics and sirna Facilities, Proteomics Core Facility, SNP Genotyping Core Other Facilities - Cardiovascular Imaging and Clinical Research Core Laboratory, Electronics Shop, Hereditary Cancer Core (Siteman Cancer Ctr), High Throughput Screening Core, Chemical Genetics and sirna Facilities, Electronics Core, Hope Center Viral Vectors Core, Health Behavior and Outreach Core (Siteman Cancer Center). PHS 398 (Rev. 11/07) Page 6 Resources Format Page

7 OVERVIEW OF THE ADRC AND OVERALL PROGRESS REPORT (5/1/05-2/28/09) GLOSSARY: A glossary of commonly used abbreviations in this application is provided here. Grants: Washington University ADRC Alzheimer Disease Research Center (P50 AG05681; JC Morris, PI) HASD Healthy Aging and Senile Dementia program project (P01 AG03991; JC Morris, PI) ACS Adult Children Study program project (P01 AG026276; JC Morris, PI) to study antecedent biomarkers of Alzheimer s disease DIAN Dominantly Inherited Alzheimer Network (U01 AG032438; JC Morris, PI) to study mutation carriers and noncarriers in familial Alzheimer s disease Affiliated ADNI Alzheimer Disease Neuroimaging Initiative (U01 AG24904; MW Weiner, PI), a consortium to evaluate imaging and biomarker changes in Alzheimer s disease ADCS Alzheimer Disease Cooperative Study (U01 AG10483; PS Aisen, PI), a consortium to advance treatment trials for Alzheimer disease LOAD Genetics Consortium for Late Onset Alzheimer s Disease (U24 AG026395, R Mayeux, PI) ADGC Alzheimer s Disease Genetics Consortium (U01 AG032984, G Schellenberg, PI) NACC National Alzheimer s Coordinating Center (U01 AG016976, W Kukull, PI), the data repository for all Alzheimer s Disease Centers (ADCs) funded by the National Institute on Aging () Definitions: AD Alzheimer s disease, defined as the histopathologic disorder regardless of the presence or absence of symptoms (e.g., mild cognitive impairment [MCI] or dementia) DAT Dementia of the Alzheimer type, the clinically diagnosed symptomatic stage of AD Preclinical AD Histopathological AD in cognitively normal individuals (i.e., in the absence of even MCI) MAP Memory and Aging Project, the clinical research office providing clinical and psychometric assessments for all participants enrolled in the ADRC, HASD, ACS, and (at Washington University) DIAN studies Aβ amyloid-beta protein, a 38 to 43 amino acid product of the amyloid precursor protein APOE/APOE PSEN1 The gene when mutated that most commonly causes AD (~164 pathogenic mutations) PSEN2 A homologue of PSEN1 (~10 pathogenic mutations causing AD) APP The gene for amyloid precursor protein (~28 pathogenic mutations causing AD) Procedures/Instruments: CDR Clinical Dementia Rating, the clinical global rating instrument to determine the absence (CDR=0) or presence (CDR=>0.5) of dementia and, when present, its severity UDS Uniform Data Set, the clinical and cognitive batteries in use at all ADCs for the standard and uniform longitudinal assessment of nondemented individuals and those with MCI and DAT LP Lumbar puncture, by which cerebrospinal fluid (CSF) is obtained MRI Magnetic resonance imaging; the sequences obtained in the ADRC and its affiliated studies comprise the Common Anatomic Protocol (CAP). PET Positron emission tomography PIB Pittsburgh Compound-B, a [ 11 C] benzothiazole amyloid imaging agent Active Total Registry Note: All assessments (initial and longitudinal) and research-related expenses for an individual participant are charged only to the grant in which that individual is enrolled. Each grant (e.g., ADRC and HASD) is budgetarily distinct from each other. The Clinical and Neuropathology Core assessment protocols for ADRC and HASD intentionally are identical and are conducted by the same personnel. The uniform assessment promotes synergism by allowing participants and their data from one grant to be available for projects supported by another grant. Hence, the overall data base of the Total Registry (ADRC and HASD combined) is larger and more useful than would be possible for any single grant to achieve. Nonetheless, participant enrollment and expenses and associated reporting are linked directly to the grant responsible for that individual s recruitment All participants, cognitively normal and demented, enrolled in the ADRC Clinical Core (i.e., the Cohort) plus those enrolled in the HASD Clinical Core, as both Cores use identical assessment protocols in a uniform manner Page 7

8 and are not included in another grant. All budgetary aspects described in this competitive renewal application are unique to the ADRC, without duplication or overlap of charges with HASD or any other grant. 1. INTRODUCTION 1.1 Scientific Themes The Washington University Alzheimer s Disease Research Center (ADRC), continuously funded by the National Institute on Aging () since 1985, fosters a range of innovative science that advances cutting-edge research on Alzheimer s disease and related conditions. The ADRC provides the infrastructure, resources, and environment to foster and enhance interdisciplinary research on the clinical and neurobiological aspects of neurodegenerative dementing disorders and nondemented aging. The ADRC also provides a fertile training environment for students, postdoctoral fellows, and junior faculty to develop investigative skills necessary to conduct interdisciplinary clinical or basic research relevant to Alzheimer s disease. The ADRC has recruited young and established investigators to the field, promoted and implemented collaborative research activities with other investigators and programs internal and external to Washington University, and actively engaged in the transfer of information to scientists, health care professionals, and the public in regional, national, and international forums. Historically, the ADRC s overarching scientific themes have been to: explore the earliest symptomatic stages of Alzheimer s disease (AD) in comparison with nondemented aging and to understand the underlying pathobiology of Alzheimer s disease. This competing renewal continues the integrated pursuit of these themes and extends the second to the evaluation of candidate biomarkers for AD, including those that may mark the disease process antecedent to the appearance of symptoms (i.e., preclinical AD). To accomplish these aims, the application proposes the continuation of 6 Cores and 2 Satellites and 3 new projects. The projects each are led by junior faculty (2 are Assistant Professors of Neurology, the other is an Instructor in the Division of Neuropathology in the Department of Pathology and Immunology). Dr. Perrin (Project 1) and Dr. Miller (Project 2) both are new to the field and neither has received NIH R01 grant support. Project 1 will explore novel biomarkers for AD in the cerebrospinal fluid (CSF) proteome in individuals with early-stage DAT in comparison with cognitively healthy older adults and will also assess the predictive power of these biomarkers in healthy elders for the development of DAT; this Project uses resources from the Clinical, Data Management and Statistics, and Genetics Cores. Project 2 will assess in transgenic mouse models of AD and frontotemporal dementia whether decreasing tau levels and altering tau isoform relationships with antisense oligonucleotides will benefit behavior and pathology; this Project uses the resources of the Data Management and Statistics Core. Project 3 will determine the in vivo metabolism of APOE in the central nervous system and assess isoform-dependent changes that may relate to the pathophysiology of AD; it uses resources from the Clinical, Data Management and Statistics, Neuropathology, and Genetics Cores. Together with the ongoing and planned studies of the ADRC and its affiliated grants, these highly innovative Projects all address the major themes of our program: 1) Distinguish the earliest symptomatic stages of AD from cognitively healthy aging. 2) Explore AD pathobiology with the ultimate aim of developing mechanism-based therapeutic strategies. 3) Develop novel biomarkers for AD that identify the disease process regardless of clinical status to improve understanding of the earliest pathogenesis of AD and the chronology of the resulting molecular, cellular, and biochemical abnormalities. A comparison of Cores and projects in the current funding cycle and those proposed in this application underscores both the stability of the ADRC and its ability to incorporate and promote cutting-edge neuroscience (Figure 1). Figure 1. Leadership of Current and Proposed ADRC Components Current (5/1/05-4/30/10) Renewal (5/1/10-4/30/15) Cores: Cores: John C Morris, Director & PI John C Morris, Director & PI (Eugene Johnson, David (Eugene Johnson, David Holtzman, Alison Goate, Administrative Holtzman, Assoc. Directors Associate Directors; Virginia Buckles, Executive Virginia Buckles, Executive Director) Director) Clinical John C Morris John C Morris African American Dorothy Edwards Monique Willliams Outreach Satellite Page 8

9 Data Management/ Statistics J Philip Miller Chengjie Xiong Neuropathology Daniel W. McKeel,Jr Nigel Cairns Education Thomas Meuser James Galvin Rural Education and Outreach Satellite Thomas Meuser James Galvin Genetics Alison Goate Alison Goate Projects 1. Mapping substrate/gamma secretase interactions; Raphael Kopan 2. Unfunded 3. PET amyloid imaging in the elderly to evaluate DAT risk; Mark Mintun Projects 1. Novel protein biomarkers for Alzheimer s disease in cerebrospinal fluid; Richard Perrin 2. Changing tau protein levels and tau protein isoforms in mouse models of dementia; Timothy Miller 3. APOE metabolism in AD and controls; Randall Bateman 1.2 Relationship of ADRC with affiliated grants With this renewal application, the ADRC integrates its considerable resources and innovative research with three closely related grants: the HASD program project, the ACS program project, and the DIAN cooperative agreement. HASD developed from the initial dementia research program (R01 MH31504, L Berg,PI) at Washington University that began in 1979 and the program project has been continuously funded since 1984 (HASD has been successfully renewed for years beginning in 2009). Since 1985 HASD has been complemented by the ADRC. Although each program is distinct scientifically and budgetarily, they share a common infrastructure to enhance standardization of assessment protocols, avoid the unnecessary costs and confusion of parallel but separate mechanisms, policies, and protocols to accomplish the same goals, and to increase the capacity of both grants to conduct research, obtain biospecimens, and complete clinicopathological studies with a larger Total Registry than either grant alone could achieve. Moreover, having the same leadership in common Cores results in notable synergies, efficiencies, and economies of scale. The Cores that are unique to one program are available to serve the other. For example, Core F: Genetics in the ADRC provides genotyping and DNA banking for HASD participants and the Imaging Core of HASD provides the CAP in the 3T magnetic resonance scanner for ADRC participants. Although ADRC and HASD are mutually beneficial, each has its own unique hypotheses and specific aims and stands on its own merits. Consequently, each has its own External Advisory Committee (no overlap of members). The budgets for each are nonoverlapping; each budget is justified only for effort specific to the activities supported by that grant. In the past 2 funding cycles, HASD has focused on clinical, cognitive, imaging, genetics, and biofluid indicators that distinguish the earliest stages of dementia of the Alzheimer type (DAT) from cognitively healthy aging and evaluates whether those same indicators are present in some healthy older adults as potential antecedent biomarkers for AD. Based on our clinicopathological studies, 1,2 we propose that a preclinical (presymptomatic) stage of AD occurs in 20%-40% of cognitively normal older adults and hypothesize that if these individuals continue to live, they are at very high risk for developing DAT. The ACS program project evolved directly from HASD to address when during the lifespan the biomarkers for preclinical AD may develop and in what order. ACS has virtually the same protocols and projects as HASD (ACS adds an amyloid imaging project) but assesses a unique cohort of cognitively normal middle age (45-74y) individuals, where half are offspring of a parent who developed DAT before age 80y. ACS was awarded a competitive supplement for a project examining a special group of adult children, those who are offspring of a parent with a deterministic mutation for AD in the APP, PSEN1, and PSEN2 genes. This Familial Adult Children Study (FACS) and the ACS were progenitors of the recently awarded DIAN cooperative agreement, which will establish a registry of ~400 offspring of individuals with a known mutation causing AD across 10 sites in the United States, United Kingdom, and Australia. DIAN participants (mutation carriers and noncarriers) largely will be unaffected, thus making the DIAN cohort ideally suited to evaluate the chronobiology of antecedent biomarkers for preclinical AD in early-onset, familial AD individuals. With this competing renewal application, ADRC now combines with the tightly integrated grants and research projects of HASD, ACS, and DIAN to identify novel biomarkers for AD in both cognitively normal individuals with preclinical AD and those who are symptomatic with DAT. Page 9

10 Figure 2 shows the relationships of ADRC, HASD, ACS, and DIAN. Figure 2 2. RESPONSE TO SUMMARY STATEMENT FOR LAST RENEWAL. The Summary Statement (release date 12/2/04) from the ADRC s last competing renewal provided a favorable review with a priority score of 153. In the Resume and Summary of Discussion, there were 4 perceived weaknesses (the critiques of individual components are addressed in the relevant sections of this competing renewal application). 2.1 potential concern that the enrolled subjects may be insufficient to support all of the planned projects or may be called on to join too many projects. This concern is more fully addressed in Core B: Clinical. Since 1985, the ADRC Clinical Core always has been successful in meeting the recruitment goals of the projects it supports. For example, in the first 4 years of the current funding period for the ADRC the Core already has provided more than the 100 total participants requested by current Project 3 for PET PIB imaging. The capacity of the Core in meeting the recruitment needs of the projects is augmented by the availability of HASD participants in the Total Registry who are eligible for and willing to enroll in ADRC studies. As also addressed in Core B Clinical, we monitor participant burden very carefully. We appreciate that we ask our participants to complete many studies, including those considered to be invasive (i.e., lumbar puncture), so we enroll only those individuals who are eligible for each and in principle are willing to complete them all. Hence, we preselect individuals who are highly committed to our research. With the extraordinary support provided by Core staff, our dedicated participants engage in and complete these studies at a high rate. Our participant retention rate of 84% at 4 years and our voluntary autopsy rate of 78% provide evidence that we do not overburden our participants. 2.2 Project 1 is high risk and overly ambitious. This high-risk project developed strategies that allow for the selection of true Notch sparing gammasecretase inhibitors in HTS assays. Such reagents will accomplish chronic reduction of APP proteolysis while permitting Notch proteolysis to continue unimpeded. Intermediate HTS assays have been developed, Page 10

11 validated, and licensed to industry (Merck, through collaboration with D. Piwnica-Worms on CA094056). Presentation of our assay at the ICAD meeting in Chicago in 2008 introduced our solution to Boehringer Ingelheim and Astra Zeneca. The robustness and dynamic range of the assay are steadily improving, and we anticipate delivering the improved screening method to industry by the end of the funding period. To perform a screen ourselves will require additional funds. In addition, several basic science projects were completed. We illuminated unique aspects of presenilin biology and described a gamma-secretase independent presenilin activity, conserved from plants to humans. We also described Nicastrin-independent activities of gamma-secretase in mammalian cells. 1. A. Khandelwal, D. Chandu, C. M, Roe, R. Kopan, R. and R. Quatrano (2007). Moonlighting Activity Of Presenilin In Plants Is Independent Of G-Secretase And Evolutionarily Conserved. PNAS 104: M. R. Hass, C. Sato R. Kopan and G. Zhao (2008). Presenilin: RIP and Beyond. Seminars in Cell & Developmental Biology 20: M.X.G, Ilagan, S. Lim, M. Blandford, D.Piwnica-Worms and R. Kopan (2009). Real-Time Imaging Of Notch Activation In Live Cells Using A Luciferase Complementation-Based Reporter. (In preparation). 4. G. Zhao, D. Chandu, M.X.G, Ilagan, R. Kopan (2009). SPP Topology Revealed By Cysteine Crosslinking (in preparation) 5. G. Zhao, Z. Liu, M.X.G, Ilagan, R. Kopan (2009). Nicastrin Independent Gamma-Secretase Activity. (in preparation) 6. C. Sato, G. Zhao, M. Blandford, D. Piwnica-Worms, R. Kopan M.X.G. Ilagan (2010). Simultaneous, Realtime Imaging of Notch and APP Proteolysis in Live Cells using Dual Color Luciferase Complementation Reporters (2010). (In preparation). 2.3 Project 2 s PI is inexperienced with AD subjects, with the very serious concern that AD patients will not be able to perform the required protocol The reviewers were incorrect; Dr. Buckner was and is very experienced with AD individuals and was Leader of HASD s Imaging Core at the time of the ADRC competing renewal. Moreover, he demonstrated unequivocally that AD participants were able to complete the protocol without difficulty (and was awarded an independent R01 for the same project). Unfortunately, this demonstration came as he left Washington University for a faculty position at Harvard University. Hence, the ADRC in the current funding period has only 2 projects, Project 1 and Project Project 3 s estimated conversion rate from normal to CDR 0.5 is too high, hence the main goal will not be attained. The jury still is out on this concern. In the remaining year of funding in the current cycle, we will test the main hypothesis of Project 3 that elevated mean cortical binding potential for PIB in cognitively healthy elders will predict those who become impaired at CDR 0.5 (or higher). The PIB imaging studies already have been enormously influential in our studies of antecedent biomarkers for preclinical AD RELATION TO WASHINGTON UNIVERSITY 3.1 Governance The ADRC is based administratively in the Department of Neurology at Washington University School of Medicine (WUSM). Dr. Morris, the Principal Investigator (PI), reports to the Head of Neurology, David Holtzman, MD, who reports to Larry Shapiro, MD, Dean of WUSM and Vice Chancellor for Medical Affairs at Washington University. Budgetary management of the ADRC is carried out by the Executive Director, Virginia Buckles, who reports to the PI; the project manager, Linda Amos, assists Dr. Buckles. Budgetary supervision is provided by the Department of Neurology. Fund transfers are made for investigators in other departments. Departmental, WUSM, and University support for the ADRC remains extraordinarily strong (Dr. Holtzman is an Associate Director for the ADRC; see Letters from Dean Shapiro and from Chancellor Wrighton). 3.2 Environment WUSM occupies 4.5 million square feet on its St. Louis campus; of this, 2.1 million square feet are devoted to research. WUSM combines with Barnes-Jewish Hospital (BJH), St. Louis Children s Hospital, and the Central Institute for the Deaf to form the Washington University Medical Center (WUMC), occupying 230 acres along the eastern edge of Forest Park. Along the western edge of the Park is the Danforth Campus housing the other Schools of Washington University, including the School of Arts and Sciences and its Department of Psychology (home of Dr. Storandt, leader of the psychometric section of Core B: Clinical). Three miles separate the Medical Center and Danforth Campuses; regularly scheduled free shuttles connect the Campuses. The WUSM components of ADRC are all within 5-10 minutes walking distance of each other. Dr. Morris office is in the Memory and Aging Project (MAP), which occupies >5000 square feet of clinical research space in a University-owned medical office building on the WUMC campus that offers free drive-up parking and Page 11

12 accessible entrances for our elderly participants. The Administration and Clinical Cores are in MAP, which serves as the clinical research office (clinical and psychometric assessments) for the ADRC and its affiliated grants. Drs. Galvin and Ms. Coats of the Clinical Cores also have offices in MAP, as does the ADRC Executive Director, Dr. Buckles. ADRC meetings and conferences, including the weekly Clinical Conference, are held in our MAP conference room. Both WUSM and BJH annually are ranked in the top tier of medical schools and hospitals in the U.S. Both feature superb facilities and programs (See Resources for the ADRC). In fiscal 2008, WUSM ranked 6 th among the 123 U.S. medical schools with $440 million in research funds from the National Institutes of Health, including 744 research grants. Included in the research funding is a neuroscience blueprint award (Washington University Center for Translational Neuroscience, P30 NS057105, D Holtzman, PI) and an Institute of Clinical and Translational Sciences (ICTS; UL1RR024992, KL2RR024994, TL1RR024995, K Polonsky, PI). 3.3 Cooperation with other programs and departments The ADRC has a longstanding tradition of interdisciplinary cooperation and collaboration among faculty and departments. The Core, Satellite, and Project Leaders in this application, for example, represent 5 departments: Neurology, Biostatistics, Pathology and Immunology, Medicine (Geriatrics), and Psychiatry. 3.4 Leadership Leonard Berg, MD, was the original PI of ADRC. Dr. Morris developed his clinical research career with Dr. Berg s mentorship. Morris joined the HASD program project in its first year (1984) and had a pilot project in the initial ADRC funding period in Morris and Johnson assumed joint leadership of ADRC in 1997 in a planned transition (Berg retired from the fulltime faculty in 1998). The collaborative, interdisciplinary approach originally established by Dr. Berg, a hallmark of the ADRC, enabled Dr. Johnson and Morris to work effectively and productively as Co-Directors until Morris became Director and PI in 2003 Coherence in the ADRC stems from its remarkably stable leadership over the years. Drs. Morris, Johnson, and Storandt have been with the ADRC since its inception; Ms. Coats, assistant Clinical Core director, joined Dr. Morris in Dr. Buckles joined Dr. Morris in 1992 as his research associate and assumed the executive director position for the ADRC in Dr. Goate, Associate Director and Leader of the Genetics Core, also joined Washington University and the ADRC in Drs. Berg and Morris recruited Dr. Holtzman, Associate Director, to Washington University in Our ADRC investigators work together in an extremely collegial and productive manner. Virtually all ADRC publications feature authors from multiple Cores and projects. In the current and proposed funding periods, the ADRC elevates some of its mid-level and junior faculty to leadership roles, reflecting the success of the training and career development environment provided by the ADRC. We were able to plan for the gradual transition of leadership in 2 Cores for which the original leader was either retiring or assuming other responsibilities, and were fortunate to have highly qualified individuals to step in as leaders of another Core and of Satellite where the change in leadership was less anticipated. Professor J. Philip Miller, original leader of Core C: Data Management and Statistics and Dr. Morris recruited Chengjie Xiong, PhD, to Washington University in 2001 with the goal of eventually succeeding Professor Miller as leader of the Core. Dr. Xiong already has been a major asset to our program with his expertise in multivariate analyses and longitudinal statistical methodologies. He is completing a mentored career development award (K25 AG025189) with Dr. Morris as his mentor and Professor Miller as co-mentor, in which he gained familiarity with and understanding of our clinical and cognitive methods and language. Professor Miller prepared Dr. Xiong for Core leadership over several years and Dr. Xiong successfully transitioned to Core Leader in June In preparation for the impending retirement of Dr. Daniel W. McKeel, Leader of Core D: Neuropathology in the last competing renewal application, Dr. Nigel J. Cairns was recruited to Washington University in 2004 to undergo a transition period with Dr. McKeel. Dr. Cairns became Core Leader in June, 2005, as Dr. McKeel retired and has maintained and enhanced the Core s activities and services. He also brings a new research emphasis to study protein misfolding in neurodegenerative disorders. Dr. Thomas Meuser, Leader of Core E: Education and of the Core s Rural Education and Outreach Satellite, left Washington University in August 2007 to take a tenure-track position as Director of Gerontology at the University of Missouri, St. Louis. Fortunately, Dr. James Galvin, Associate Leader of the Clinical Core in the last competing renewal, had worked closely for years with the Education Core in its educational programming and outreach services. After a brief transition period of 3 months prior to Dr. Meuser s departure, Dr. Galvin assumed leadership of the Core and Satellite in 2007 and has excelled in these roles. Indeed, at the September 2008 meeting of the Education Core Leaders for all ADCs, Dr. Galvin was elected as Chair of their Steering Committee. Page 12

13 The Clinical Core s African American Outreach Satellite (AAOS) has been led by its inception in 1992 by Dr. Dorothy Edwards. As an African American clinical investigator in HASD, Dr. Monique Williams, Assistant Professor of Medicine in the Division of Geriatrics, frequently interacted with Dr. Edwards and the Satellite team. Indeed, Dr. Williams over the years provided much support for the AAOS in its mission of increasing awareness of AD among the African American community in St. Louis and in increasing the number of African Americans recruited to the ADRC. When Dr. Edwards took a sabbatical leave in 2006 at the University of Wisconsin, Dr. Williams served as interim Leader of the Satellite. Dr. Edwards then decided to permanently join the faculty at the University of Wisconsin and Dr. Williams was the ideal choice to replace her as the Satellite Leader in PROGRESS REPORT/ADRC PRODUCTIVITY 4.1 Publications In the last competing renewal, the ADRC was pleased to report 213 publications that were directly related to the Center during the previous funding period. We now report 368 ADRC-related publications for this funding period (see Overview Bibilography following Literature Cited). Although only a very few are highlighted here, the quality and number of these publications place the ADRC among the leading Alzheimer programs nationally and internationally. Particular areas of strength include the discrimination of the earliest symptomatic stages of AD from cognitively normal aging, the development of imaging, genetic, and CSF markers to identify preclinical AD, and the unique method to study in vivo metabolism of proteins believed to be important in the pathogenesis of AD. Storandt M et al, Longitudinal course and neuropathological outcomes in original versus revised MCI 9 and in PreMCI. Relative to published criteria for amnestic MCI and for revised criteria MCI, we examined the psychometric performances (obtained independently of the clinical assessment that determined CDR status and diagnosis) of 379 CDR 0.5 participants who we diagnosed as having very mild DAT. Our sample was comparable to published MCI samples for age, education, sex distribution, APOE genotype, level of cognitive impairment as measured by the Mini Mental State Examination (MMSE) and by the Sum Boxes of the Clinical Dementia Rating (CDR), and frequency and types of comorbid disorders. Our sample thus does not have unique characteristics. Where we differ from other studies of MCI is in our approach to the assessment and classification of the sample. Our clinical detection method focuses on the principle of intraindividual decline in cognitive abilities necessary to conduct everyday activities at accustomed levels. Informant observations, coupled with a clinical interview with the participant, are used by an experienced clinician to assess intraindividual decline, whereas MCI characterizations rely on a comparison of an individual s psychometric performance with normative values. The interindividual comparison of cognitive test performance (individual vs. norms) captures neither individual decline nor interference with accustomed activities. We found that 32 of our 379 CDR 0.5/DAT participants fulfilled criteria for amnestic MCI, 90 met revised criteria for MCI, and 276 were too minimally impaired on psychometric performance to meet any MCI criteria and thus represented a premci stage. All three groups (amnestic MCI, revised criteria MCI, and premci) in our series progressively declined in clinical severity and psychometric performance over a 16 year study period. Median survival to CDR 1 (mild DAT) was about 4 years for the 2 CDR 0.5/DAT groups meeting MCI criteria and about 7 years for the CDR 0.5/DAT group that was premci. Seventy-six individuals from all 3 groups combined came to autopsy and histopathological AD was confirmed in 70 (92%). It is clear that DAT can be detected accurately at a stage even earlier than MCI if emphasis is placed on intraindividual decline rather than on interindividual comparisons of psychometric test performances with group norms. Galvin JE et al, The AD8: A brief informant interview to detect dementia 10 Using principal component analysis of the Clinical Core s semi-structured interview of informants to assess intraindividual change in participants, an 8-item questionnaire, the Ascertain Dementia 8 (AD8), provides good to excellent discrimination between CDR 0 and CDR 0.5 (AUC=0.834). The AD8, which takes about 2 minutes to complete, is useful in clinical as well as research settings (Neurology 2006; 67: ), 11 can be selfcompleted (Archives of Neurology 2007; 64: ), 12 and can be combined with Word List Recall for even greater sensitivity and sensitivity to predict dementia with 92% correct classification (Archives of Neurology 2007; 64: ). 13 Fagan AM et al, Decreased cerebrospinal fluid Aβ 42 correlates with brain atrophy in cognitively normal elderly. 14 In CSF assays from 69 cognitively normal individuals, levels of CSF tau and ptau 181, but not Aβ 42, correlate inversely with whole brain volume in mild DAT. However, CSF levels of Aβ 42, but not tau or ptau 181, are positively correlated with whole brain volume in cognitively normal persons. These findings suggest that cerebral Aβ deposition has toxic brain effects in preclinical AD, prior to the appearance of DAT (consistent with Page 13

14 Fotenos et al, Neurology 2008; 65: ), 15 and that increases in CSF tau and ptau 181 are later events that occur with clinical onset and progression of DAT. Buckner RL et al, Molecular, structural, and functional characterization of Alzheimer s disease: Evidence 16 for a relationship between default activity, amyloid, and memory. Data from 5 in vivo imaging methods indicate a convergence of effects in posterior cortical regions that show prominent atrophy, metabolic abnormalities, and elevated PIB binding in older adults with DAT. These same regions correspond to those that are more active during rest or in a passive condition and represent the hypothetical default mode of human cognition. It is possible that lifelong cerebral metabolism in the default network predisposes these regions to AD pathology. Bateman RJ et al, Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo 17 This report describes the first and only method to quantify in vivo protein synthesis and clearance rates in the human central nervous system. It is being used to assess differences in metabolism for Aβ and other proteins that may contribute to AD (as proposed in Project 3 of this competing renewal application) and to evaluate treatments for pharmacodynamic effects on proposed disease pathways (Bateman RJ et al, A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system, Annals of Neurology, in press). 4.2 Project Productivity Project 1, Mapping substrate/gamma secretase interactions, Raphael Kopan, Project Leader, will terminate at the end of the current funding period. Its productivity and publications are detailed in Section 2.2 (above). The assay developed in this Project already has been licensed to industry. Project 3, PET amyloid imaging in the elderly to evaluate DAT risk, Mark Mintun, Project Leader, has been enormously successful as described in Section 2.4 (above). Although it will terminate as an ADRC project at the close of the current funding period, it has already been leveraged into multiple new funded projects (e.g., Project 1 of HASD; Project 1 of ACS; Imaging Core of DIAN). Additional grant submissions are pending. The impact of Project s 3 productivity is illustrated in a manuscript (under review), entitled, APOE genotype predicts Aβ but not tau pathology in cognitively normal aging by Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, and Mintun MA. Two hundred and forty-one cognitively normal individuals, age 45y-88y, from ADRC, HASD, and ACS, had PET PIB by Project 3 in this funding period. Elevated mean cortical binding potential (MCBP) for PIB increased after age 55y as a function of age and APOE genotype, such that were noncarriers (Figure 3A). The presence of one or more APOE2 allele protected against elevated MCBP with age (Figure 3B). The same data for APOE4 are shown in Figure 4 A where a MCBP>0.18 is arbitrarily designated as PIB-positive. Figure 4B shows, in 168 of the 241 cognitively normal individuals who also had CSF assays, that reduced CSF Aβ 42 levels also shows an age and an APOE4 effect but appears to begin at a slightly earlier age than elevated MCBP for PIB. (There was no APOE effect for CSF tau or ptau 181, only an age effect such that levels gradually increased). These data suggest that cerebral Aβ 42 deposition is the pathobiological phenotype for APOE4 and suggests that Aβ abnormalities, rather than tau changes, initiate the pathological cascade of preclinical AD. Figure 3a Figure 3b PIB Mean Cortical Binding Potential APOEε4+ PIB Mean Cortical Binding Potential APOEε4- APOEε2- APOEε Age, y Age, y Page 14

15 Figure 4a % PIB+ 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% 0.0% APOEε4- APOEε4+ APOEε4- APOEε % 8.2% 36.7% 15.6% 52.9% 16.0% (39) (28) (49) (30) (45) (17) (25) (8) Age, y 75.0% Figure 4b 4.3 Pilot Project Productivity Since the submission of the last ADRC competing renewal in May 2004, 18 ADRC Pilot grants have resulted in 30 refereed publications and have been used to generate $18,335,000 in new grants (11 NIH R01s, 4 NIH R21s or R33s, 2 NIH K awards, 1 NSF award, and 9 foundation or industry awards. Two of the Projects in this competing renewal application stemmed directly from ADRC Pilot grant awards. Dr. Bateman (Project 3) initiated his pioneering studies of in vivo metabolism of Aβ with a Pilot award in Dr. Miller (Project 2) submitted a Pilot grant application in 2008 (funded as of 5/1/09) to develop antisense oligonucleotides to modify tau in mouse models of dementia. Dr. Miller originally had focused on mechanisms involved in amyotrophic lateral sclerosis, but interactions with Drs. Holtzman and Goate after he was recruited to Washington University in 2007 encouraged him to broaden his interests to AD. Hence, he built on the work proposed in his ADRC Pilot to develop the major experiments now proposed in Project ADRC Support of Projects, Grants, and Trainees ADRC resources during the current funding period have been used to support 83 federal grants (Table 1), 113 nonfederal grants (Table 2), and 18 industry-sponsored therapeutic trials (Table 3). Thirteen individuals associated with the ADRC have received 17 training awards (Table 4) The ADRC is strongly supportive of multicenter collaborative studies (Table 5), including NACC, ADCS, ADNI, LOAD, and ADGC. The ADRC contributes tissue to the National Cell Repository of Alzheimer s Disease. Dr. Morris chairs the Clinical Task Force for the ADCs and was instrumental in the development of the Uniform Data Set (UDS) that now is used by all ADCs in the longitudinal assessment of normal aging, MCI, and AD. 18 The ADRC is strongly committed to encouraging diversity in its investigators, staff, and participants. Table 6 lists minority-related grants to ADRC investigators. The entire Clinical Core of the ADRC underwent training in cultural competency and sensitivity in Private funding The ADRC, its Director, and its Associate Directors work closely with Washington University s Office of Development and Alumni Affairs to seek philanthropic support. In the past two years, these efforts have generated over $1,000,000 per year to support ADRC research initiatives, retain faculty, recruit new faculty, and seed pilot investigations. 4.6 Core A: Administration The productivity of the Core s Pilot grant program, including the generation of over $18 million in new grants, is noted in Section (above). The successful transition of leadership of the Data Management and Statistics Core, the Education Core, the Rural Education and Outreach Satellite, and the African American Outreach Satellite in the current funding period is noted in Section 3.4 (above) The Core actively engaged in the recruitment of Dr. Catherine Roe to the Clinical Core, Dr. Gina D Angelo to the Data Management and Statistics Core, Dr. Nupur Ghoshal to the Genetics Core, and Dr. Beau Ances to Washington University (See Administration Core). The data sharing initiatives of the ADRC are numerous and extensive (see Tables 1-3 for documentation of tissue and data sharing with internal and external investigators). The Open Access Series of Imaging Studies (OASIS) is an excellent demonstration of how the ADRC and its affiliated grants make freely and publicly available anonymized data from our imaging studies to support research Core B: Clinical % CSF Aβ % 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% 9.7% 21.7% 16.7% 43.5% 23.3% 63.6% 45.5% Age, y 66.7% (31) (23) (36) (23) (30) (11) (11) (3) Page 15

16 The Core exceeded its recruitment goals for the current funding period and provided ample numbers of participants to Project 3 and other studies supported by the Core. Ninety-eight percent of ADRC participants contribute DNA, 64% have CAP, 56% have lumbar puncture for CSF, and 34% have PET PIB. In the past 2 years, (8/06 through 7/08), 25% of new enrollees to the Core have been African American; African Americans now represent over 12% of the total Cohort. Our 4-year retention rate for participants is 84%. Autopsies were obtained in 88 individuals out of 114 deaths (78%). Clinical diagnostic accuracy rate for DAT is high (100% in last reporting year). The Core contributed to over 130 refereed publications since the last competing renewal was submitted. 4.8 Core C: Data Management and Biostatistics Dr. D Angelo joined the Core in Core personnel contributed to or consulted on 198 separate ADRC investigations in the current funding period. Core personnel are authors or co-authors on 43 peer-reviewed manuscripts from the ADRC in the same period, including reports of novel statistical methodology developed by the Core. The Core also was closely involved with the development (study design, sample size determinations, analytic plans) for all 3 Projects in this competing renewal application. The Core is positioning the entire ADRC to migrate to the bioinformatics platforms, catissue and ClinPortal, within the next year. 4.9 Core D: Neuropathology The Core accessions well over its goal of 25 brains per year. It has increased the collection of frozen tissue from these brains to 97%. It has reduced the postmortem interval from 15.1h in the last funding cycle to 11.9h in the current cycle. Most importantly, it has distributed tissue to 30 investigators, both within and outside of Washington University, to support research studies. The Core Leader not only has modernized the tissue processing methods to the Core to better support research, he is at the forefront of research advances in the characterization of frontotemporal lobar degeneration. His laboratory reported the first mutation in the gene encoding for TDP In recognition of his neuropathological skills, he and Dr. Morris in 2007 were awarded a competitive supplement by the to establish a Neuropathology Core at Washington University for the Alzheimer s Disease Neuroimaging Initiative Core E: Education The Core provided training to over 19,000 lay and professional individuals in the current funding cycle. It worked cooperatively with the African American Outreach Satellite of the Clinical Core and with the African American Advisory Board of the ADRC to improve minority recruitment. It has productive collaborations with many organizations, including the St. Louis Chapter of the Alzheimer s Association with which it developed and implemented a curriculum for Dementia Friendly Hospitals. The Core maintains the website that provides training in the Clinical Dementia Rating (which has been translated into 68 languages) for numerous studies, including NACC, the Alzheimer s Disease Cooperative Study, and industry-sponsored clinical trials. The Core co-sponsors with other components of the ADRC the highly successful biennial Leonard Berg Symposium. The Rural Education and Outreach Satellite of the Core provides the innovative Clinicians Partners Program, offering rural health professionals an in-depth educational experience on dementia and aging. It also sponsors research regarding driving and dementia. Finally, it maintains the Alzheimer s List, the oldest based Internet support group for Alzheimer caregivers Core F: Genetics The Core provided genotype and other data to 39 federally supported investigators and 27 non-federally support grants, as well as to 14 trainees in the current funding period. The Core has been a leader in using CSF protein levels as an endophenotype to detect novel genetic risk factors for AD. It recruits extended kindreds for genetic studies of dementia, and identified the progranulin mutations causing Hereditary Disinhibition Dysphasic Dementia (frontotemporal lobar degeneration) in 2 families. 20 The genetic studies of the Core helped to parent the successful development of the ACS and DIAN grants. 5. SUMMARY OF THE APPLICATION The Cores and Satellites of the ADRC provide an exceptionally supportive and established infrastructure to enable the Projects to accomplish their aims. The highly innovative Projects in this proposal are led by talented junior investigators, all of whom are supported in their career development by the ADRC. The ADRC for 25 years has supported and conducted novel and highly influential research on AD. In the proposed funding period it will provide unique contributions from its Projects that offer new lines of research to advance understanding of the preclinical etiology of AD (Projects 1 and 3), explore potential new therapeutic targets for AD (Project 2), and better define the transition from cognitively normal aging to the earliest symptomatic stages of AD (Projects 1, 2, and 3). The ADRC provides an ideal environment to enhance the cutting-edge research proposed by these Projects. Page 16

17 The mature ADRC remains dedicated to fostering and promoting novel and important research on AD and related disorders at Washington University and beyond and has been extraordinarily successful in doing so (Tables 1-3). It remains a leader in the AD field; as one example, its assessment tool, the CDR, has been adopted by the UDS as the clinical global staging scale for all ADCs and it is the standard clinical scale worldwide, having been translated into 68 languages. With this competing renewal application, the ADRC continues its history of excellence by extending its research to antecedent biomarkers for preclinical AD. Indeed, a key component of this work, as proposed in Project 3 of this application, can only be accomplished at our ADRC. With its companion grants (HASD, ACS, and DIAN), the ADRC offers an unparalleled number of integrated, interdisciplinary, and innovative studies to examine the clinical, cognitive, imaging, biochemical, and molecular abnormalities related to AD pathogenesis. 6. BIBLIOGRAPHY 1. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol 1999; 45: Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;(In Press) 3. Mintun MA, LaRossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [ 11 C] PIB in a nondemented population: Potential antecedent marker of Alzheimer disease. Neurology 2006; 67: Fagan AM, Mintun MA, Mach RH, Lee S-Y, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann Neurol 2006; 59: Fagan AM, Roe CM, Xiong C, Morris JC, Holtzman DM. Cerebrospinal fluid tau/ß-amyloid 42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007; 64: Roe CM, Xiong C, Grant E, Miller JP, Morris JC. Education and reported onset of symptoms among individuals with Alzheimer's disease. Arch Neurol 2008; 65: Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD; regional thinning predicts mild AD dementia. Neurology 2009; 72: Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts AB but not tau Alzheimer's pathology in cognitively normal aging. Ann Neurol. 2009;(In Press) 9. Storandt M, Grant EA, Miller JP, Morris JC. Longitudinal course and neuropathological outcomes in original versus revised MCI and in PreMCI. Neurology 2006; 67: Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, Miller JP, Storandt M, Morris JC. The AD8:A brief informant interview to detect dementia. Neurology 2005; 65: Galvin JE, Roe CM, Xiong C, Morris J.C. Validity and reliability of the AD8 informant interview in dementia. Neurology 2006; 67: Galvin JE, Roe CM, Coats MA, Morris JC. Patient's rating of cognitive ability: using the AD8, a brief informant interview as a self rating tool to detect dementia. Arch Neurol 2007; 64: Galvin JE, Roe CM, Morris JC. Evaluation of cognitive impairment in older adults; combining brief informant and performance measures. Arch Neurol 2007; 64: Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, Holtzman DH. Decreased cerebrospinal fluid AB42 correlates with brain atrophy in cognitively normal elderly. Ann Neurol 2009; 65: Fotenos AF, Mintun MA, Snyder AZ, Morris JC, Buckner RL. Brain volume decline in aging: evidence for a relationship between socioeconomic status, preclinical Alzheimer's disease, and reserve. Arch Neurol 2008; 65: Buckner RL, Snyder AZ, Shannon BJ, Larossa G, Sachs R, Fotenos AF, Sheline Y, Klunk W, Mathis C, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005; 25: Page 17

18 17. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 2006; 12: Morris JC, Weintraub S, Chui HC, Cummings J, DeCarli C, Ferris S, Foster NL, Galasko D, Graff-Radford NR, Peskind ER, Beekly D, Ramos EM, Kukull WA. The Uniform Data Set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alz Dis Assoc Disord 2006; 20: Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 2008; 63: Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JSK, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu P-H, Grinberg LT, Liscic RM, Armendariz J, Morris JC, Goate AM. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of Progranulin. Ann Neurol 2006; 60: B Summary Publication List for Center as a Whole, n=368 total. These publications are divided into three lists: List 1: publications authored or co-authored by Center investigators using Center resources, n=214 List 2: publications using Center resources (subjects, data, and tissue) but not authored by Center Personnel, n=97 List 3: publications authored by Center investigators but not directly using Center resources, n=57. List 1: publications authored or co-authored by Center investigators using Center resources, n= Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology 2009; 72: Balsis S, Carpenter BD, Storandt M. Personality change precedes clinical diagnosis of dementia of the Alzheimer type. J Gerontol B Psychol Sci Soc Sci 2005; 60: Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 2006; 12: Bateman RJ, Munsell LY, Chen X, Holtzman DM, Yarasheski KE. Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates. J Am Soc Mass Spectrom 2007; 18: PMC Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 2007; 68: Behrens MI, Mukherjee O, Tu PH, Liscic RM, Grinberg LT, Carter D, Paulsmeyer K, Taylor-Reinwald L, Gitcho M, Norton JB, Chakraverty S, Goate AM, Morris JC, Cairns NJ. Neuropathologic heterogeneity in HDDD1: a familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation. Alzheimer Dis Assoc Disord 2007; 21: Behrens MI, Roe CM, Morris JC. Inverse association between cancer and dementia of the Alzheimers type. Neurodegenerative Diseases: From Molecular Concepts to Therapeutic Targets. 2009: In Press 8. Blom ES, Holmans P, Arepalli S, Adighibe O, Hamshere ML, Gatz M, Pedersen NL, Bergem ALM, Owen MJ, Hollingworth P, Goate A, Williams J, Lannfelt L, Hardy J, Wavrant-DeVrieze F, Glaser A. Does APOE explain the linkage of Alzheimer s disease to chromosome 19q13? Am J Med Genet B Neuropsychiat Genet 2008; 147B: Brendza RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DM. Anti-AΒ antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 2005; 115: PMC Page 18

19 10. Brown PJ, Woods CM, Storandt M. Model stability of the 15-item Geriatric Depression Scale across cognitive impairment and severe depression. Psychol Aging 2007; 22: Buckner RL, Head D, Parker J, Fotenos AF, Marcus D, Morris JC, Snyder AZ. A unified approach for idwest tric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage 2004; 23: Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005; 25: Burns JM, Morris JC. Hypotension and dementia risk in the elderly. Journal Watch Neurology 2004; 6: Burns JM, Galvin JE, Roe CM, Morris JC, McKeel DW. The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 2005; 64: Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF, Snyder AZ, Morris JC, Buckner RL. White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 2005; 62: Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF, Snyder AZ, Morris JC, Buckner RL. White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer s disease. Arch Neurol 2005; 62: Burns JM, Cronk BB, Anderson HS, Donnelly JE, Thomas GP, Harsha A, Brooks WM, Swerdlow RH. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology 2008; 71: Burns JM, Morris JC. Mild Cognitive Impairment and Early Alzheimer s Disease: Detection and Diagnosis. West Sussex, England: John Wiley & Sons, Ltd., Busby V, Goossens S, Nowotny P, Hamilton G, Smemo S, Harold D, Turic D, Jehu L, Myers A, Womick M, Woo D, Compton D, Doil LM, Tacey KM, Lau KF, Al Saraj S, Killick R, Pickering-Brown S, Moore P, Hollingworth P, Archer N, Foy C, Walter S, Lendon C, Iwatsubo T, Morris JC, Norton J, Mann D, Janssens B, Hardy J, O Donovan M, Jones L, Williams J, Holmans P, Owen MJ, Grupe A, Powell J, van Hengel J, Goate A, Van Roy F, Lovestone S. Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer s disease. Neuromolecular Med 2004; 5: Cacchione PZ, Powlishta KK, Grant EA, Buckles VD, Morris JC. Collateral source reports in very mild to mild dementia of the Alzheimer type. In: Vellas B, Fitten LJ, Winblad B, Feldman H, Grundman M, Giacobini E et al., editors. Research and Practice in Alzheimer Disease. Paris: Serdi Publishers, 2004: Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL, III, Schneider JA, Kretzschmar HA, Carter D, Taylor-Reinwald L, Paulsmeyer K, Strider J, Gitcho M, Goate AM, Morris JC, Mishra M, Kwong LK, Stieber A, Xu Y, Forman MS, Trojanowski JQ, Lee VM, Mackenzie IR. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 2007; 171: PMC Cam JA, Zerbinatti CV, Knisely JM, Hecimovic S, Li Y, Bu G. The low density lipoprotein receptorrelated protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. J Biol Chem 2004; 279: Cam JA, Zerbinatti CV, Li Y, Bu G. Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein. J Biol Chem 2005; 280: Carpenter BD, Xiong C, Porensky EK, Lee MM, Brown PJ, Coats M, Johnson D, Morris JC. Reaction to a dementia diagnosis in individuals with Alzheimer s disease and mild cognitive impairment. J Am Geriatr Soc 2008; 56: Carr DB, Shead V, Storandt M. Driving cessation in older adults with dementia of the Alzheimer s type. Gerontologist 2005; 45: Ceyhan E, Beg MF, Ceritoglu C, Wang L, Morris JC, Csernansky JG, Miller MI, Ratnanather JT. Statistical analysis of metric distances between hippocampal shapes to predict the rates of shape changes in dementia of Alzheimer type and nondemented subjects. IEEE Transactions on Medical Engineering. 2007;(In Press) Page 19

20 27. Corbett J, Saccone NL, Foroud T, Goate A, Edenberg H, Nurnberger J, Porjesz B, Begleiter H, Reich T, Rice JP. A sex-adjusted and age-adjusted genome screen for nested alcohol dependence diagnoses. Psychiatr Genet 2005; 15: Costa DA, Cracchiolo JR, Bachstetter AD, Hughes TF, Bales KR, Paul SM, Mervis RF, Arendash GW, Potter H. Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms. Neurobiol Aging 2007; 28: Creeley CE, Wozniak DF, Bayly PV, Olney JW, Lewis LM. Multiple episodes of mild traumatic brain injury result in impaired cognitive performance in mice. Acad Emerg Med 2004; 11: Croston J, Meuser TM, Berg-Weger M, Grant B, Carr DB. Driving cessation in older adults with dementia. Topics in Geriatric Rehabilitation. 2009;(In Press) 31. Csernansky JG, Hamstra J, Wang L, McKeel D, Price JL, Gado M, Morris JC. Correlations between antemortem hippocampal volume and postmortem neuropathology in AD subjects. Alzheimer Dis Assoc Disord 2004; 18: Csernansky JG, Wang L, Miller JP, Galvin JE, Morris JC. Neuroanatomical predictors of response to donepezil therapy in patients with dementia. Arch Neurol 2005; 62: Csernansky JG, Martin M, Shah R, Bertchume A, Colvin J, Dong H. Cholinesterase inhibitors amerliorate behavioral deficits induced by MK-801 in mice. Neuropsychopharmacology 2005; 30: PMC Csernansky JG, Wang L, Swank J, Miller JP, Gado M, McKeel D, Miller MI, Morris JC. Preclinical detection of Alzheimer s disease: hippocampal shape and volume predict dementia onset in the elderly. Neuroimage 2005; 25: Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, Morris JC. Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 2006; 163: PMC Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, Grodstein F, Wright CI, Blacker D, Rosas HD, Sperling RA, Atri A, Growdon JH, Hyman BT, Morris JC, Fischl B, Buckner RL. The cortical signature of Alzheimer s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloidpositive individuals. Cereb Cortex 2009; 19: PMC Dickerson BC, Feczko E, Augustinack JC, Pacheco J, Morris JC, Fischl B, Buckner RL. Differential effects of aging and Alzheimer s disease on medial temporal lobe cortical thickness and surface area. Neurobiol Aging 2009; 30: Dobbs BM, Carr DB. Screening and assessment of medically at-risk drivers. Pulbic Policy and Aging Report 2005; 15: Dunckley T, Beach TG, Ramsey KE, Grover A, Mastroeni D, Walker DG, LaFleur BJ, Coon KD, Brown KM, Caselli R, Kukull W, Higdon R, McKeel D, Morris JC, Hulette C, Schmechel D, Reiman EM, Rogers J, Stephan DA. Gene expression correlates of neurofibrillary tangles in Alzheimer s disease. Neurobiol Aging 2006; 27: PMC Duyckaerts C, Potier M-C, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol 2008; 115:5-38 PMC Edwards DF, Morris JC. Alone and confused: Community-residing older African Americans with dementia. Dementia 2007; 6: Evason K, Huang C, Yamben I, Covey DF, Kornfeld K. Anticonvulsant medications extend worm lifespan. Science 2005; 307: Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, Larossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 2006; 59: Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/betaamyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007; 64: Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Medication use as a confounding factor in the use of the cerebrospinal fluid tau/β-amyloid42 ratio-reply. Arch Neurol 2007; 64: Page 20

21 47. Fagan AM, Head D, Shah AR, Marcus D, Mintun M, Morris JC, Holtzman DM. Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 2009; 65: Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Encinas JM, Serrano J, Bentura ML, Munoz P, Martinez-Murillo R, Rodrigo J. Expression of nitric oxide system in clinically evaluated cases of Alzheimer s disease. Neurobiol Dis 2004; 15: Fernandez-Vizarra P, Fernandez AP, Castro-Blanco S, Serrano J, Bentura ML, Martinez-Murillo R, Martinez A, Rodrigo J. Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer s disease. Histol Histopathol 2004; 19: Fleisher AS, Raman R, Siemers ER, Clark CM, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Shezai AD, Aisen PS, Thal LJ. Phase II trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer s disease. Arch Neurol 2008; 65: Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri BS, Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD, Kimonis VE. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 2006; 65: Fotenos AF, Snyder AZ, Girton LE, Morris JC, Buckner RL. Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 2005; 64: Fotenos AF, Mintun MA, Snyder AZ, Morris JC, Buckner RL. Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol 2008; 65: Galvin JE, Ginsberg SD. Expression profiling and pharmacotherapeutic development in the central nervous system. Alzheimer Dis Assoc Disord 2004; 18: Galvin JE. Neurodegenerative diseases: pathology and the advantage of single-cell profiling. Neurochem Res 2004; 29: Galvin JE, Powlishta KK, Wilkins K, McKeel DW, Jr., Xiong C, Grant E, Storandt M, Morris JC. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch Neurol 2005; 62: Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, Miller JP, Storandt M, Morris JC. The AD8: a brief informant interview to detect dementia. Neurology 2005; 65: Galvin JE, Ginsberg SD. Expression profiling in the aging brain: a perspective. Ageing Res Rev 2005; 4: Galvin JE. Cognitive change in Parkinson disease. Alzheimer Dis Assoc Disord 2006; 20: Galvin JE, Pollack J, Morris JC. Clinical phenotype of Parkinson disease dementia. Neurology 2006; 67: Galvin JE, Roe CM, Xiong C, Morris JC. Validity and reliability of the AD8 informant interview in dementia. Neurology 2006; 67: Galvin JE, Malcom H, Johnson D, Morris JC. Personality traits distinguishing dementia with Lewy bodies from Alzheimer disease. Neurology 2007; 68: Galvin JE. Improving behavioral and cognitive outcomes in Alzheimer disease: evolving strategies. Applied Neurology 2007; February supplement: Galvin JE, Roe CM, Coats MA, Morris JC. Patient s rating of cognitive ability: using the AD8, a brief informant interview, as a self-rating tool to detect dementia. Arch Neurol 2007; 64: Galvin JE, Roe CM, Morris JC. Evaluation of cognitive impairment in older adults: combining brief informant and performance measures. Arch Neurol 2007 ; 64 : Galvin JE, Meuser TM, Coats MA, Bakal DA, Morris JC. The portable CDR: translating the clinical dementia rating interview into a PDA format. Alzheimer Dis Assoc Disord 2009 ; 23 : Galvin JE, Meuser TM, Boise L, Connell CM. Determinants of physician referral for patient recruitment to Alzheimer disease clinical trials. Alz Dis Assoc Disord. 2009;(In Press) 68. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL, III, Bigio EH, Caselli R, Baker M, Al Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 2008; 63: Goate A. Segregation of a missense mutation in the amyloid-β protein precursor gene with familial Alzheimer s disease. J Alz Dis 2006; 9: Page 21

22 70. Goate A. Segregation of a missense mutation in the amyloid-β protein precursor gene with familial Alzheimer s disease. In: Jucker M, Beyreuther K, Haass C, Nitsch R, Christen Y, editors. Alzheimer: 100 Years and Beyond, Research and Perspectives in Alzheimer s Disease. Berlin Heidelberg: Springer-Verlag, 2006: Gold BT, Balota DA, Cortese MJ, Sergent-Marshall SD, Snyder AZ, Salat DH, Fischl B, Dale AM, Morris JC, Buckner RL. Differing neuropsychological and neuroanatomical correlates of abnormal reading in early-stage semantic dementia and dementia of the Alzheimer type. Neuropsychologia 2005; 43: Gomez RG, White DA. Using verbal fluency to detect very mild dementia of the Alzheimer type. Arch Clin Neuropsychol 2006; 21: Green PS, Mendez AJ, Jacob JS, Crowley JR, Growdon W, Hyman BT, Heinecke JW. Neuronal expression of myeloperoxidase is increased in Alzheimer s disease. J Neurochem 2004; 90: Green PS, Bales K, Paul S, Bu G. Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer s disease. Endocrinology 2005; 146: Grupe A, Li Y, Rowland C, Hinrichs T, Holmans P, Hardy J, O Donovan M, Owen MJ, Williams J, Goate A. Reply to Bertram et al. Am J Hum Genet 2006; 79: Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrieze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A. A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. Am J Hum Genet 2006; 78:78-88 PMC Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, Jehu L, Segurado R, Stone D, Schadt E, Karnoub M, Nowotny P, Tacey K, Catanese J, Sninsky J, Brayne C, Rubinsztein D, Gill M, Lawlor B, Lovestone S, Holmans P, O Donovan M, Morris JC, Thal L, Goate A, Owen MJ, Williams J. Evidence for novel susceptibility genes for late-onset Alzheimer s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 2007; 16: Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, Wiener H, Rochberg N, Tanzi RE, Myers A, Wavrant-DeVrieze F, Go R, Fallin D, Lovestone S, Hardy J, Goate A, O Donovan M, Williams J, Owen MJ. Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer s disease. Human Molecular Genetics 2007; 16: Hashemzadeh-Bonehi L, Phillips RG, Cairns NJ, Mosaheb S, Thorpe JR. Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Exp Neurol 2006; 199: Hass MR, Sato C, Kopan R, Zhao G. Presenilin: RIP and beyond. Semiinars in Cell and Developmental Biology 2008; 81. Hatanpaa KJ, Bigio EH, Cairns NJ, Womack KB, Weintraub S, Morris JC, Foong C, Xiao G, Hladik C, Mantanona TY, White CL, III. TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a idwest-southwest consortium for FTLD study. J Neuropathol Exp Neurol 2008; 67: PMC Head D, Snyder AZ, Girton LE, Morris JC, Buckner RL. Frontal-hippocampal double dissociation between normal aging and Alzheimer s disease. Cereb Cortex 2005; 15: Hecimovic S, Wang J, Dolios G, Martinez M, Wang R, Goate AM. Mutations in APP have independent effects of AΒ and CTFy generation. Neurobiology of Disese 2004; 17: Hollingworth P, Hamshere ML, Holmans PA, O Donovan MC, Sims R, Powell J, Lovestone S, Myers A, DeVrieze FW, Hardy J, Goate A, Owen M, Williams J. Increased familial risk and genomewide significant linkage for Alzheimer s disease with psychosis. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: Holmans P, Hamshere M, Hollingworth P, Rice F, Tunstall N, Jones S, Moore P, DeVrieze FW, Myers A, Crook R, Compton D, Marshall H, Meyer D, Shears S, Booth J, Ramic D, Williams N, Norton N, Abraham R, Kehoe P, Williams H, Rudrasingham V, O Donovan M, Jones L, Hardy J, Goate A, Lovestone S, Owen M, Williams J. Genome screen for loci influencing age at onset and rate Page 22

23 of decline in late onset Alzheimer s disease. Am J Med Genet B Neuropsychiat Genet 2005; 135: Holtzman DM. In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. J Mol Neurosci 2004; 23: Hu Y, Malone JP, Fagan AM, Townsend RR, Holtzman DM. Comparative proteomic analysis of intraand interindividual variation in human cerebrospinal fluid. Mol Cell Proteomics 2005; 4: Hu Y, Hosseini A, Kauwe JSK, Gross J, Cairns NJ, Goate AM, Fagan AM, Townsend RR, Holtzman DM. Identification and validation of novel CSF proteomic biomarkers for early stages of Alzheimer s disease. Clin Proteomics. 2007;(In Press) 89. Hughes SE, Evason K, Xiong C, Kornfeld K. Genetic and pharmacological factors that influence reproductive aging in Nematodes. PLOS Genetics 2007; 3:e25.doi: journal.pgen PMC Johnson DK, Morris JC, Galvin JE. Verbal and visuospatial deficits in dementia with Lewy bodies. Neurology 2005; 65: Johnson DK, Wilkins CH, Morris JC. Accelerated weight loss may precede diagnosis in Alzheimer disease. Arch Neurol 2006; 63: Johnson DK, Storandt M, Morris JC, Langford ZD, Galvin JE. Cognitive profiles in dementia: Alzheimer disease vs healthy brain aging. Neurology 2008; 71: Johnson DK, Storandt M, Morris J, Galvin JE. Longitudinal study of the transition from healthy aging to Alzheimer disease. Arch Neurol. 2009;(In Press) 94. Johnson J, Ostojic J, Lannfelt L, Glaser A, Basun H, Rogaeva E, Kawarai T, Bruni A, St.George-Hyslop PH, Goate A, Pastor P, Chakraventy S, Norton J, Morris J.C., Hardy J, Singleton A. No evidence for tau duplication in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found. Neurosci Res. 2004;(In Press) 95. Karnik M, Wang L, Barch DM, Morris JC, Csernansky JG. BDNF polymorphism rs6265 and hippocampal structure and memory performance in healthy control subjects. Psych Res. 2008;(In Press) 96. Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, Holtzman DM, Morris JC, Goate AM. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer s disease presenilin 1 mutation. Ann Neurol 2007; 61: Kauwe JS, Wang J, Chakraverty S, Goate AM, Henao-Martinez AF. Novel presenilin 1 variant (P117A) causing Alzheimer s disease in the fourth decade of life. Neurosci Lett 2008; 438: Kauwe JS, Cruchaga C, Mayo K, Fenoglio C, Bertelsen S, Nowotny P, Galimberti D, Scarpini E, Morris JC, Fagan AM, Holtzman DM, Goate AM. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proc Natl Acad Sci U S A 2008; 105: PMC Kauwe JSK, Wang J, Mayo K, Morris JC, Fagan AM, Holtzman DM, Goate AM. Alzheimer s disease risk variants show association with cerebrospinal fluid amyloid beta. Neurogenetics 2009; 10: Keller PC, Tomita T, Hayashi I, Chandu D, Weber JD, Cistola DP, Kopan R. A faster migrating variant masquerades as NICD when performing in vitro gamma-secretase assays with bacterially expressed Notch substrates. Biochemistry 2006; 45: PMC Khandelwal A, Chandu D, Roe CM, Kopan R, Quatrano RS. Moonlighting activity of presenilin in plants is independent of y-secretase and evolutionary conserved. PNAS 2007; 104: PMC Kilada S, Gamaldo A, Grant EA, Moghekar A, Morris JC, O Brien RJ. Brief screening tests for the diagnosis of dementia: comparison with the mini-mental state exam. Alzheimer Dis Assoc Disord 2005; 19: Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, Savitcheva I, Huang G- F, Estrada S, Ausén B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Långström B. Imaging brain amyloid in Alzheimer s disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: Legleiter J, Czilli DL, Gitter B, Demattos RB, Holtzman DM, Kowalewski T. Effect of different anti-abeta antibodies on Abeta fibrillogenesis as assessed by atomic force microscopy. J Mol Biol 2004; 335: Page 23

24 105. Legleiter J, Demattos RB, Holtzman DM, Kowalewski T. In situ AFM studies of astrocyte-secreted apolipoprotein E- and J-containing lipoproteins. J Colloid Interface Sci 2004; 278: Li Y, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Lau K, Catanese J, Sninsky J, Nowotny P, Holmans P, Hardy J, Powell J, Lovestone S, Thal L, Owen M, Williams J, Goate A, Grupe A. Association of ABCA1 with late-onset Alzheimer s disease is not observed in a case-control study. Neurosci Lett 2004; 366: Li Y, Nowotny P, Holmans P, Smemo S, Kauwe JS, Hinrichs AL, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Gogic G, Chan J, Cravchik A, Ross D, Lau K, Kwok S, Chang SY, Catanese J, Sninsky J, White TJ, Hardy J, Powell J, Lovestone S, Morris JC, Thal L, Owen M, Williams J, Goate A, Grupe A. Association of late-onset Alzheimer s disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci U S A 2004; 101: Li Y, Rowland C, Tacey K, Catanese J, Sninsky J, Hardy J, Powell J, Lovestone S, Morris JC, Thal L, Goate A, Owen M, Williams J, Grupe A. The BDNF val66met polymorphism is not associated with late onset Alzheimer s disease in three case-control samples. Molecular Psychiatry 2005; Li Y, Hollingworth P, Moore P, Foy C, Archer N, Powell J, Nowotny P, Holmans P, O Donovan M, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Lau K, Cantanese J, Sninsky J, Hardy J, Thal L, Morris JC, Goate A, Lovestone S, Owen M, Williams J, Grupe A. Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease. Hum Mutat 2005; 25: Li Y, Grupe A, Rowland C, Nowotny P, Kauwe JS, Smemo S, Hinrichs A, Tacey K, Toombs TA, Kwok S, Catanese J, White TJ, Maxwell TJ, Hollingworth P, Abraham R, Rubinsztein DC, Brayne C, Wavrant-De Vrieze F, Hardy J, O Donovan M, Lovestone S, Morris JC, Thal LJ, Owen M, Williams J, Goate A. DAPK1 variants are associated with Alzheimer s disease and allelespecific expression. Hum Mol Genet 2006; 15: Li Y, Rowland C, Catanese J, Morris J, Lovestone S, O Donovan MC, Goate A, Owen M, Williams J, Grupe A. SORL1 variants and risk of late-onset Alzheimer s disease. Neurobiol Dis 2008; 29: PMC Li Y, Grupe A, Rowland C, Holmans P, Segurado R, Abraham R, Jones L, Catanese J, Ross D, Mayo K, Martinez M, Hollingworth P, Goate A, Cairns NJ, Racette BA, Perlmutter JS, O Donovan MC, Morris JC, Brayne C, Rubinsztein DC, Lovestone S, Thal LJ, Owen MJ, Williams J. Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer s and Parkinson s disease. Hum Mol Genet 2008; 17: Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Walker DG, Caselli RJ, Kukull WA, McKeel D, Morris JC, Hulette C, Schmechel D, Alexander GE, Reiman EM, Rogers J, Stephan DA. Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiol Genomics 2007; 28: PMC Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA. Alzheimer s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 2008; 105: PMC Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli R, Kukull WA, McKeel D, Morris JC, Hulette CM, Schmechel D, Reiman EM, Rogers J, Stephan DA. Neuronal gene expression in non-demented individuals with intermediate Alzheimer s Disease neuropathology. Neurobiol Aging. 2008;(In Press) 116. Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA, McKeel D, Morris JC, Hulette CM, Schmechel D, Reiman EM, Rogers J, Stephan DA. Altered neuronal gene expression in brain regions differentially affected by Alzheimer s disease: a reference data set. Physiol Genomics 2008; 33: Lim WS, Rubin EH, Coats M, Morris JC. Early-stage Alzheimer disease represents increased suicidal risk in relation to later stages. Alzheimer Dis Assoc Disord 2005; 19: Lim WS, Liscic RM, Xiong CJ, Morris JC. High dose vitamin E supplemention: time to return to the drawing board. Letter to the Editor: A reply to Meta-Analysis: High-dosage vitamin E supplementation may incease all-cause mortality. Ann Intern Med 2005; 143:152 Page 24

25 119. Liscic RM, Storandt M, Cairns NJ, Morris JC. Clinical and psychometric distinction of frontotemporal and Alzheimer dementias. Arch Neurol 2007; 64: Liscic RM. How to differentiate frontotemporal from Alzheimer s dementia? Recent developments in molecular genetics and neuropathology. Zdrav Vestn 2008; 77: Liscic RM, Grinberg LT, Zidar J, Gitcho MA, Cairns NJ. ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol 2008; 15: Mackay A, Connor LT, Storandt M. Dementia does not explain correlation between age and scores on Boston Naming Test. Arch Clin Neuropsychol 2005; 20: Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM, Trojanowski JQ. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007; 61: Malmstrom TK, Miller DK, Coats MA, Jackson P, Miller JP, Morris JC. Informant-based dementia screening in a population-based sample of African Americans. Alz Dis Assoc Disord. 2009;(In Press) 125. Marcus DS, Wang TH, Parker J, Csernansky JG, Morris JC, Buckner RL. Open Access Series of Imaging Studies (OASIS): cross-sectional MRI data in young, middle aged, nondemented, and demented older adults. J Cogn Neurosci 2007; 19: Marcus DS, Olsen TR, Ramaratnam M, Buckner RL. The Extensible Neuroimaging Archive Toolkit: an informatics platform for managing, exploring, and sharing neuroimaging data. Neuroinformatics 2007; 5: Marwit SJ, Meuser TM, Bryer D. Development of an awareness context theory typology for addressing communications patterns in mild dementia. The Clinical Gerontologist 2005; 28: Marwit SJ, Meuser TM. Development of a short form inventory to assess grief in caregivers of dementia patients. Death Studies 2005; 29: McKeel DW, Price JL, Miller JP, Grant EA, Xiong C, Berg L, Morris J.C. Neuropathologic criteria for diagnosing Alzheimer Disease in persons with pure dementia of Alzheimer type. J Neuropathol Exp Neurol 2004; 63: McKeel DW, Burns JM, Meuser TM, Morris JC. Dementia: An Atlas of Investigation and Diagnosis. Oxford: Clinical Publishing, Meuser TM, Carr DB, Berg-Weger M, Niewoehner P, Morris JC. Driving and dementia in older adults: Implementation and evaluation of a continuing education project. Gerontologist 2006; 46: Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006; 67: Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, Chio A, Fung HC, Holtzman DM, Huey ED, Wassermann EM, Adamson J, Hutton ML, Rogaeva E, George-Hyslop P, Rothstein JD, Hardiman O, Grafman J, Singleton A, Hardy J, Traynor BJ. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS- FTD. BMC Neurol 2006; 6:44 PMC Momeni P, Cairns NJ, Perry RH, Bigio EH, Gearing M, Singleton AB, Hardy J. Mutation analysis of patients with neuronal intermediate filament inclusion disease (NIFID). Neurobiol Aging. 2006;(In Press) 135. Morikawa M, Fryer JD, Sullivan PM, Christopher EA, Wahrle SE, Demattos RB, O Dell MA, Fagan AM, Lashuel HA, Walz T, Asai K, Holtzman DM. Production and characterization of astrocytederived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta. Neurobiol Dis 2005; 19: Morris J.C. Antecedent Biomarkers in Alzheimer s Disease II: Uses, Limitations, and Future Directions for Research ; Morris JC. Targeting MCI: the benefits of early intervention. Practical Neurology 2004; 3: Morris JC. Early-stage and preclinical Alzheimer disease. Alzheimer Dis Assoc Disord 2005; 19: Morris JC, Storandt M. Detecting early-stage Alzheimer s disease in MCI and PreMCI: The value of informants. In: Jucker M, Beyreuther K, Haass C, Nitsch R, Christen Y, editors. Alzheimer: 100 Page 25

26 Years and Beyond, Research and Perspectives in Alzheimer s Disease. Heidelberg: Springer- Verlag Berlin Heidelberg, 2006: Morris JC. Perspectives on two decades for Alzheimer Disease and Associated Disorders, An International Journal. Alz Dis Assoc Disord 2006; 20: Morris JC. Profile: beating dementia through prevention. The Lancet Neurology 2008; 7: Mosaheb S, Thorpe JR, Hashemzadeh-Bonehi L, Bigio EH, Gearing M, Cairns NJ. Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease. Acta Neuropathol 2005 ; 110 : PMC Mosconi L, Tsui W-H, de Santi S, Li J, Rusinek H, Convit A, Li Y, Boppana M, de Leon MJ. Reduced hippocampal metabolism in MCI and AD; automated FDG-PET image analysis. Neurology 2005; 64: Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz GL, Liscic RM, Armendariz J, Morris JC, Goate AM. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 2006; 60: Mukherjee O, Kauwe JS, Mayo K, Morris JC, Goate AM. Haplotype-based association analysis of the MAPT locus in late onset Alzheimer s disease. BMC Genet 2007; 8:3 PMC Mukherjee O, Wang J, Gitcho M, Chakraverty S, Taylor-Reinwald L, Shears S, Kauwe JS, Norton J, Levitch D, Bigio EH, Hatanpaa KJ, White CL, Morris JC, Cairns NJ, Goate A. Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 2008; 29: Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor JP, Kretzschmar HA, Kimonis VE, Forman MS. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 2007; 66: Norton JB, Cairns N, Galvin JE, Goate A. Presenilin 1 g217r mutation linked to alzheimer s disease with cotton wool plaques. Neurology. 2009;(In Press) 149. Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell T, Holmans P, Hamshere M, Turic D, Jehu L, Hollingworth P, Moore P, Bryden L, Myers A, Doil LM, Tacey KM, Gibson AM, McKeith IG, Perry RH, Morris CM, Thal L, Morris JC, O Donovan MC, Lovestone S, Grupe A, Hardy J, Owen MJ, Williams J, Goate A. Association studies between risk for late-onset Alzheimer s disease and variants in insulin degrading enzyme. Am J Med Genet B Neuropsychiatr Genet 2005; 136B: Nowotny P, Simcock X, Bertelsen S, Hinrichs AL, Kauwe JS, Mayo K, Smemo S, Morris JC, Goate A. Association studies testing for risk for late-onset Alzheimer s disease with common variants in the beta-amyloid precursor protein (APP). Am J Med Genet B Neuropsychiatr Genet 2007; 144B: Nowotny P, Bertelsen S, Hinrichs AL, Kauwe JS, Mayo K, Jacquart S, Morris JC, Goate A. Association studies between common variants in prolyl isomerase Pin1 and the risk for late-onset Alzheimer s disease. Neurosci Lett 2007; 419:15-17 PMC Pastor P, Ezquerra M, Perez JC, Chakraverty S, Norton J, Racette BA, McKeel D, Perlmutter JS, Tolosa E, Goate AM. Novel haplotypes in 17q21 are associated with progressive supranuclear palsy. Ann Neurol 2004; 56: Perkinson MA, Berg-Weger ML, Carr DB, Meuser TM, Palmer JL, Buckles VD, Powlishta KK, Foley DJ, Morris JC. Driving and dementia of the Alzheimer type: beliefs and cessation strategies among stakeholders. Gerontologist 2005; 45: Powlishta KK, Storandt M, Mandernach TA, Hogan E, Grant EA, Morris JC. Absence of effect of depression on cognitive performance in early-stage Alzheimer disease. Arch Neurol 2004; 61: Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease. Neurobiol Aging. 2009;(In Press) 156. Quick KL, Ali SS, Arch R, Xiong C, Wozniak D, Dugan LL. A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiol Aging 2008; 29: Page 26

27 157. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu- Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA. GAB2 alleles modify Alzheimer s risk in APOE epsilon4 carriers. Neuron 2007; 54: PMC Renner JA, Burns JM, Hou CE, McKeel DW, Jr., Storandt M, Morris JC. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 2004; 63: Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. Commentary on A roadmap for the prevention of dementia II: Leon Thal Symposium Prevention trials in persons at risk for dominantly inherited Alzheimer s disease: Opportunities and challenges. Alzheimer s & Dementia 2009; 5: Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology 2005; 64: Roe CM, Xiong C, Miller JP, Morris JC. Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis. Neurology 2007; 68: Roe CM, Xiong C, Miller JP, Cairns NJ, Morris JC. Interaction of neuritic plaques and education predicts dementia. Alzheimer Dis Assoc Disord 2008; 22: Roe CM, Xiong C, Grant E, Miller JP, Morris JC. Education and reported onset of symptoms among individuals with Alzheimer disease. Arch Neurol 2008; 65: Roe CM, Mintun MA, D Angelo G, Xiong C, Grant EA, Morris JC. Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol 2008; 65: Rollinson S, Rizzu P, Sikkink S, Baker M, Halliwell N, Snowden J, Traynor BJ, Ruano D, Cairns N, Rohrer JD, Mead S, Collinge J, Rossor M, Akay E, Guerreiro R, Rademakers R, Morrison KE, Pastor P, Alonso E, Martinez-Lage P, Graff-Radford NR, Neary D, Heutink P, Mann DM, Van Swieten JC, Pickering-Brown SM. Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. Neurobiol Aging 2009; 30: Rubin EH. Cognitive disorders: dementia. In: Rubin EH, Zorumski CF, editors. Adult Psychiatry. Blackwell Publishing, 2005: Sanders S, Marwit SJ, Meuser TM, Harrington P. Caregiver grief in end-stage dementia: using the Marwit and Meuser caregiver grief inventory for assessment and intervention in social work practice. Social Work in Health Care 2007; 46: Saori H, Fukshige S, Araki Y, Kato N, Araseki M, Sakuma M, Taniguchi M, Urakami K, Akatsu H, Hartmann D, Fahrenholz F, Yamamoto K, Martins RNMM, Nishimura M, Levey A, Chung KA, Montine T, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya T, Gandy S, Suzuki T. Peptides produced by covariant processing of APP and alcadein implicate γ-secretase dysfunction in sporadic Alzheimer s disease. Neuron 2009; In press 169. Schymick JC, Yang Y, Andersen PM, Vonsattel JP, Greenway M, Momeni P, Elder J, Chio A, Restagno G, Robberecht W, Dahlberg C, Mukherjee O, Goate A, Graff-Radford NR, Caselli RJ, Hutton M, Gass J, Cannon A, Rademakers R, Singleton AB, Hardiman O, Rothstein J, Hardy J, Traynor BJ. Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosisfrontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatry 2007; 78: Shah KR, Carr D, Roe CM, Miller JP, Coats M, Morris JC. Impaired physical performance and the assessment of dementia of the Alzheimer type. Alzheimer Dis Assoc Disord 2004; 18: Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, Zoulnouni P, Galvin JE, Holtzman DM, Knopman DS, Satterwhite J, Gonzales C, Dean RA, May PC. Effects of a y-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 2006; 66: Smemo S, Nowotny P, Hinrichs AL, Kauwe JS, Cherny S, Erickson K, Myers AJ, Kaleem M, Marlowe L, Gibson AM, Hollingworth P, O Donovan MC, Morris CM, Holmans P, Lovestone S, Morris JC, Thal L, Li Y, Grupe A, Hardy J, Owen MJ, Williams J, Goate A. Ubiquilin 1 polymorphisms are not associated with late-onset Alzheimer s disease. Ann Neurol 2006; 59: Snider BJ, Norton J, Coats MA, Chakraverty S, Hou CE, Jervis R, Lendon CL, Goate AM, McKeel DW, Jr., Morris JC. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life. Arch Neurol 2005; 62: Page 27

28 174. Snider BJ, Fagan AM, Roe CM, Shah AR, Grant EA, Xiong C, Morris JC, Holtzman DM. CSF biomarkers predict rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol. 2008;(In Press) 175. Song SK, Kim JH, Lin SJ, Brendza RP, Holtzman DM. Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition. Neurobiol Dis 2004; 15: Storandt M. Use of the 5-item geriatric depression scale in demented individuals and with psychiatric outpatients. Clinical Gerontologist 2005; 28: Storandt M, Grant EA, Miller JP, Morris JC. Longitudinal course and neuropathological outcomes in original versus revised MCI and in PreMCI. Neurology 2006; 67: Storandt M. Cognitive deficits in the early stages of Alzheimer s disease. Current Directions in Psychological Science 2008; 17: Sun SW, Song SK, Harms MP, Lin SJ, Holtzman DM, Merchant KM, Kotyk JJ. Detection of agedependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer s disease using magnetic resonance diffusion tensor imaging. Exp Neurol 2005; 191: Tarawneh R, Galvin JE. Distinguishing Lewy body dementias from Alzheimer s disease. Expert Rev Neurother 2007; 7: Thorpe JR, Tang H, Atherton J, Cairns NJ. Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy. J Neural Transm 2008 ; 115 : Tirado V, Munoz C, Aguirre C, Pineda DA, Lopera F. Desempeno de portadores y no portadores de la mutacion E280A para la enfermedad de Alzheimer familiar en una prueba de denominacion. Rev Neurol 2004 ; 39 : Tu Z, Xu J, Jones LA, Li S, Dumstorff C, Vangveravong S, Chen DL, Wheeler KT, Welch MJ, Mach RH. Fluorine-18-Labeled Benzamide Analogues for Imaging the σ2 Receptor Status of Solid Tumors with Positron Emission Tomography. J Med Chem 2007; 50: Ulfarsson GF, Carr DB, Meuser TM. Motor-vehicle crash history and licensing outcomes for older drivers reported as medically impaired in Missouri accident analysis and prevention. Accident Analysis and Prevention. 2009;(In Press) 185. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocytesecreted apoe. J Biol Chem 2004; 279: Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM. Deletion of Abca1 increases Aß deposition in the PDAPP transgenic mouse model of Alzheimer disease. Journal of Biological Chemistry 2005; 280: Wahrle SE, Holtzman DM. Apolipoprotein E, amyloid β peptide, and Alzheimer s disease. In: Dawbarn D, Allen SJ, editors. Neurobiology of Alzheimer s Disease. United Kingdom: Oxford University, 2007: Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 2008; 118: PMC Walker ES, Martinez M, Wang J, Goate A. Conserved residues in juxtamembrane region of the extracellular domain of nicastrin are essential for ψ-secretase complex formation. J Neurochemistry 2006; 98: Wang J, Brunkan AL, Hecimovic S, Walker E, Goate A. Conserved PAL sequence in presenilins is essential for y-secretase activity, but not required for formation or stabilization of y-secretase complexes. Neurobiology of Disease 2004; 15: Wang J, Beher D, Nyborg AC, Shearman MS, Golde TE, Goate A. C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. J Neurochem 2006; 96: Wang JC, Grucza R, Cruchaga C, Hinrichs AL, Bertelsen S, Budde JP, Fox L, Goldstein E, Reyes O, Saccone N, Saccone S, Zuei X, Bucholz K, Kuperman S, Nurnberger J, Rice JP, Schuckit M, Tischfield J, Hesselbrock V, Porjesz B, Edenberg HJ, Bierut LJ, Goate AM. Genetic variation in Page 28

29 the CHRNA5 gene affects mrna levels and is associated with risk for alcohol dependence. Mol Psychiatr 2008; Wang L, Miller JP, Gado MH, McKeel DW, Rothermich M, Miller MI, Morris JC, Csernansky JG. Abnormalities of hippocampal surface structure in very mild dementia of the Alzheimer type. Neuroimage 2006; 30: Wang L, Beg F, Ratnanather T, Ceritoglu C, Younes L, Morris JC, Csernansky JG, Miller MI. Large deformation diffeomorphism and momentum based hippocampal shape discrimination in dementia of the Alzheimer type. IEEE Trans Med Imaging 2007; 26: Wang L, Harms MP, Stags J, Xiong C, Morris JC, Csernansky JG, Galvin JE. Treatment with Donepezil does not alter longitudinal hippocampal surface changes in mild Alzheimer disease. Arch Neurol. 2009;(In Press) 196. Wilkins CH. Alzheimer s Disease Sourcebook, 3 rd edition. J Nat Med Assoc 2005; 97: PMC Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 2006; 14: Wilkins CH, Grant EA, Schmitt SE, McKeel DW, Morris JC. The neuropathology of Alzheimer disease in African American and white individuals. Arch Neurol 2006; 63: Wilkins CH, Wilkins KL, Meisel M, Depke M, Williams J, Edwards DF. Dementia undiagnosed in poor older adults with functional impairment. J Am Geriatr Soc 2007; 55: Wilkins CH, Roe CM, Morris JC. A brief clinical tool to assess physical function in mild dementia:the Mini PPT. Arch Gerontol Geriatr. 2009;(In Press) 201. Wilkins CH, Birge SJ, Sheline YI, Morris JC. Vitamin D deficiency is associated with worse cognitive performance and lower bone density in older African Americans. J Nat Med Assoc 2009; 101: Williams MM, Xiong C, Morris JC, Galvin JE. Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease. Neurology 2006; 67: Williams MM, Roe CM, Morris JC. Stability of the Clinical Dementia Rating: Arch Neurol. 2009;(In Press) 204. Xiong C, McKeel DW, Jr., Miller JP, Morris JC. Combining correlated diagnostic tests: application to neuropathologic diagnosis of Alzheimer s disease. Med Decis Making 2004; 24: Xiong C, Miller JP, Feng G, Yan Y, Yu Q, Morris JC. Testing increasing hazard rate for the progression time of dementia. Journal of Biopharm Stat. 2004;(In Press) 206. Xiong C, Yu K, Gao F, Yan Y, Zhang Z. Power and sample size for clinical trials when efficacy is required in multiple endpoints: application to an Alzheimer s treatment trial. Clin Trials 2005; 2: Xiong C, van Belle G, Miller JP, Morris JC. Measuring and estimating diagnostic accuracy when there are three ordinal diagnostic groups. Stat Med 2006; 25: Xiong C, van Belle G, Miller JP, Yan Y, Gao F, Yu K, Morris JC. A parametric comparison of diagnostic accuracy with three ordinal diagnostic groups. Biom J 2007; 49: Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Bergmann KR, Morris JC. Assessing statistical applications in publications on Alzheimer s disease. Neuroepidemiology 2007; 28: Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Morris JC. Evaluating the quality of longitudinal statistical applications in original publications on Alzheimer s disease. Neuroepidemiology 2008; 30: Yan P, Hu X, Song H, Yin K, Bateman R, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 2006; 281: Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee JM. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 2006; 26: Zacks JM, Speer NK, Swallow KM, Braver TS, Reynolds JR. Event Perception: A Mind-Brain Perspective. Psychol Bull 2007; 133: Zanjani H, Finch CE, Kemper C, Atkinson J, McKeel D, Morris JC, Price JL. Complement activation in very early Alzheimer disease. Alzheimer Dis Assoc Disord 2005; 19: Zerbinatti CV, Bu G. LRP and Alzheimer s disease. Rev Neurosci 2005; 16: Page 29

30 List 2: publications using Center resources (subjects, data, and tissue) but not authored by Center Personnel, n=97 1. Acosta O, Bourgeat P, Fripp J, Bonner E, Ourselin S, Salvado O. Automatic delineation of sulci and improved partial volume classification for accurate 3D voxel-based cortical thickness estimation from MR. Medical Image Computing & Computer-Assisted Intervention 2008; 11: Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL. Disruption of large-scale brain systems in advanced aging. Neuron 2007; 56: Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 2004; 305: Arrate F, Younes L, Ratnanather JT. A numerical method for solving the EPDiff equation of computational anatomy. Effective computational methods for highly oscillatory problems: the interplay between mathematical theory and applications Cambridge, UK, Isaac Newton Institute of Mathematical Sciences. Ref Type: Report 5. Balota DA, Duchek JM, Sergent-Marshall SD, Roediger HL, III. Does expanded retrieval produce benefits over equal-interval spacing? Explorations of spacing effects in healthy aging and early stage Alzheimer's disease. Psychol Aging 2006; 21: Balota DA, Cortese MJ, Sergent-Marshall SD, Spieler DH, Yap MJ. Visual word recognition of singlesyllable words. J Exp Psychol 2004; 133: Bao J, Lin H, Ouyang Y, Lei D, Osman A, Kim TW, Mei L, Dai P, Ohlemiller KK, Ambron RT. Activitydependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nat Neurosci 2004; 7: Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, Revesz T, Davis MB, Wood NW, Collinge J, Tabrizi SJ. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum Mol Genet 2004; 13: Beg MF, Khan A. Symmetric data attachment terms for large deformation image registration. IEEE Transactions on Medical Imaging 2007; 26: Blaeser F, Sanders MJ, Truong N, Ko S, Wu LJ, Wozniak DF, Fanselow MS, Zhuo M, Chatila TA. Longterm memory deficits in Pavlovian fear conditioning in Ca2+/calmodulin kinase kinase alphadeficient mice. Mol Cell Biol 2006; 26: PMC Bourgeat P, Acosta O, Zuluaga M, Fripp J, Salvado O, Ourselin S. Improved cortical thickness measurement from MR images using partial volume estimation. Biomedical Imaging: From Nano To Macro, ; ISBI th IEEE International Symposium: Braver TS, Satpute AB, Rush BK, Racine CA, Barch DM. Context processing and context maintenance in healthy aging and early stage dementia of the Alzheimer's type. Psychol Aging 2005; 20: Brewer JB, Magda S, Airriess C, Smith ME. Fully-automated quantification of regional brain volumes for improved detection of focal atrophy. Am J Neuroradiol. 2009;(In Press) 14. Buckner RL. Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 2004; 44: Bugg J, Head D. Exercise moderates age-related atrophy of the medial temporal. Neurobiology of Aging In press NIHMS # Ref Type: Magazine Article 16. Carpenter BD, Kissel EC, Lee MM. Preferences and life evaluations of older adults with and without dementia: reliability, stability, and proxy knowledge. Psychol Aging 2007; 22: Castel AD, Balota DA, Hutchison KA, Logan JM, Yap MJ. Spatial attention and response control in healthy younger and older adults and individuals with Alzheimer's disease: evidence for disproportionate selection impairments in the Simon task. Neuropsychology 2007; 21: Chen CT, Wang JC, Cohen BA. The strength of selection on ultraconserved elements in the human genome. Am J Hum Genet 2007; 80: PMC Chu W, Rothfuss J, Chu Y, Zhou D, Mach RH. Synthesis and in vitro evaluation of sulfonamide Isatin Michael Acceptors as small molecule inhibitors of Caspase ; Cortese MJ, Balota DA, Sergent-Marshall SD, Buckner RL, Gold BT. Consistency and regularity in pasttense verb generation in healthy ageing, Alzheimer's disease, and semantic dementia. Cognit Neuropsychol 2006; 23: Page 30

31 21. Csernansky JG, Wang L, Joshi SC, Ratnanather JT, Miller MI. Computational anatomy and neuropsychiatric disease: probabilistic assessment of variation and statistical inference of group difference, hemispheric asymmetry, and time-dependent change. Neuroimage 2004; 23:S56-S Debjani T, Thirumangalakudi L, Grammas P. MIIP 1-α expression is elevated in Alzheimer's vessels and is regulated by oxidative and lipid stress. J Neuropathol Exp Neurol 2007; 66: Debjani T, Thirumangalakudi L, Grammas P. RANTES upregulation in the Alzheimer's disease brain: A possible neuroprotective role. Neurobiol Aging. 2009;(In Press) 24. Desikan RS, Segonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, Buckner RL, Dale AM, Maguire RP, Hyman BT, Albert MS, Killiany RJ. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006; 31: Dickerson AE, Molnar LJ, Eby DW, Adler G, Bedard M, Berg-Weger M, Classen S, Foley D, Horowitz A, Kerschner H, Page O, Silverstein NM, Staplin L, Trujillo L. Transportation and Aging: A Research Agenda for advancing safe mobility. The Gerontologist 2007; 47: Dong H, Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer's disease. Psychopharmacology (Berl) 2005; 181: PMC Dong H, Yuede CM, Yoo H-S, Martin MV, Deal C, Mace AG, Csernansky JG. Corticosterone and related receptor expression are associated with increased B-amyloid plaques in isolated Tg2576 mice. Neuroscience 2008; 155: PMC Dong H, Yuede CM, Coughlan C, Lewis B, Csernansky JG. Effects of Memantine on neuronal structure and conditioned fear in the Tg2576 mouse model in Alzheimer's disease. Neuropsychopharmacology 2008; 33: PMC Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG. Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 2004; 127: Dong H, Martin MV, Chambers S, Csernansky JG. Spatial relationship between synapse loss and B- amyloid deposition in Tg2576 mice. J Comp Neurol 2007; 500: PMC Drozdov AN, Grossfield A, Pappu RV. Role of solvent in determining conformational preferences of alanine dipeptide in water. J Am Chem Soc 2004; 126: Duchek JM, Balota DA. Failure to control prepotent pathways in early stage dementia of the Alzheimer's type: evidence from dichotic listening. Neuropsychology 2005; 19: Duchek JM, Balota DA, Cortese M. Prospective memory and apolipoprotein E in healthy aging and early stage Alzheimer's disease. Neuropsychology 2006; 20: Duchek JM, Balota DA, Storandt M, Larsen R. The power of personality in discriminating between healthy aging and early-stage Alzheimer's disease. J Gerontol B Psychol Sci Soc Sci 2007; 62: Elbert DL, Mawuenyega KG, Scott EA, Wildsmith KR, Bateman RJ. Stable isotope labeling tandem mass spectrometry (SILT): Integration with peptide identification and extension to data-dependent scans. Journal of Proteome Research 2008; 7: Evason K, Collins JJ, Huang C, Hughes S, Kornfeld K. Valproic acid extends Caenorhabditis elegans lifespan. Aging Cell 2008; 7: Faust ME, Balota DA, Multhaup KS. Phonological blocking during picture naming in dementia of the Alzheimer type. Neuropsychology 2004; 18: Feczko E, Augustinack JC, Fischl B, Dickerson BC. An MRI-based method for measuring volume, thickness and surface area of entorhinal, perirhinal, and posterior parahippocampal cortex. Neurobiol Aging 2009; 30: Fennema-Notestine C, Gamst AC, Quinn BT, Pacheco J, Jernigan TL, Thal L, Buckner R, Killiany R, Blacker D, Dale AM, Fischl B, Dickerson B, Gollub RL. Feasibility of multi-site clinical structural neuroimaging studies of aging using legacy data. Neuroinformatics 2007; 5: Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM. Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci 2005; 25: Fryer JD, Demattos RB, McCormick LM, O'Dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM. The low density lipoprotein receptor regulates the level of Page 31

32 central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem 2005; 280: Geraci L. A test of the frontal lobe functioning hypothesis of age deficits in production priming. Neuropsychology 2006; 20: Gold BT, Balota DA, Kirchoff BA, Buckner RL. Common and dissociable activation patterns associated with controlled semantic and phonological processing: evidence from fmri adaptation. Cerebral Cortex 2005; 50: Gold BT, Balota DA, Jones SJ, Powell DK, Smith CD, Andersen AH. Dissociation of automatic and strategic lexical-semantics: functional magnetic resonance imaging evidence for differing roles of multiple frontotemporal regions. J Neurosci 2006; 26: Hamilton M, Geraci L. The picture superiority effect in conceptual implicit memory: a conceptual distinctiveness hypothesis. Am J Psychol 2006; 119: Han X, Cheng H. Characterization and direct quantitation of cerebroside molecular species from lipid extracts by shotgun lipidomics. J Lipid Res 2005; 46: He Y, Chen Z, Evans A. Structural insights into aberrant topological patterns of large-scale, cortical networks in Alzheimer's disease. J Neurosci 2008; 28: Hong MG, Myers AJ, Magnusson PK, Prince JA. Transcriptome-wide assessment of human brain and lymphocyte senescence. PLoS ONE 2008; 3:e3024 PMC Huang C, Xiong C, Kornfeld K. Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans. PNAS 2004; 101: Hutchison KA, Balota DA. Decoupling semantic and associative information in false memories: explorations with semantically ambiguous and unambiguous critical lures. Journal of Memory & Language 2005; 52: Ju J-S, Miller SE, Hanson PI, Weihl CC. Impaired protein aggregate handling and clearance underlie the pathogenesis of p97/vcp associated disease. J Biol Chem 2008; 283: Kang J-E, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity. PNAS 2007; 104: PMC Khan AR, Wang L, Beg MF. FreeSurfer-initiated fully-automated subcortical brain segmentation in MRI using Large Deformation Diffeomorphic Metric Mapping. Neuroimage 2008; 41: Kissel EC, Carpenter BD. It's all in the details: physician variability in disclosing a dementia diagnosis. Aging Ment Health 2007; 11: Kurby CA, Zacks JM. Segmentation in the perception and memory of events. Trends Cog Sci 2007; 12:72-79 PMC Lach HW, Chang YP. Caregiver perspectives on safety in home dementia care. West J Nurs Res 2007; 29: Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL. Synaptic targeting by Alzheimer's-related amyloid Β oligomers. J Neurosci 2004; 24: Lee C-S, Tee LY, Warmke T, Vinjamoori A, Cai A, Fagan AM. A proteasomal stress response: pretreatment with proteasome inhibitors increases proteasome activity and reduces neuronal vulnerability to oxidative injury. J Neurochem 2004; 91: Lee J-T, Xu J, Lee J-M, Ku G, Han X, Yang D-I, Chen S, Hsu C-Y. Amyloid-Β peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 2004; 164: Lee JH, Cheng R, Graff-Radford NR, Foroud T, Mayeux R, National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group. Analyses of the National Institute on Aging late-onset Alzheimer's disease family study: implication of additional loci. Arch Neurol 2008; 65: Lee JM, Zhai G, Gonzales ER, Yin K, Yan P, Hsu CY, Vo KD, Lin W. Vascular permeability precedes spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats. Stroke 2007; 38: Lee NA, Priebe CE, Ratnanather JT, Miller MI. Validation of alternating kernal mixture method: application to segmentation of cortical and sub-cortical brain structures Human Brain Mapping presentation. Ref Type: Report Page 32

33 63. Legleiter J, Kowalewski T. Atomic force microscopy of beta-amyloid: static and dynamic studies of nanostructure and its formation. Methods Mol Biol 2004; 242: Logan JM, Balota DA. Expanded vs. equal interval spaced retrieval practice: exploring different schedules of spacing and retention interval in younger and older adults. Aging, Neuropsychology, and Cognition. 2007;(In Press) 65. Lustig C, Buckner RL. Preserved neural correlates of priming in old age and dementia. Neuron 2004; 42: Marsh EJ, Balota DA, Roediger HLI. Learning facts from fiction: the effects of healthy aging and early stage dementia of the Alzheimer's type. Neuropsychology 2005; 19: Marsh EJ, Dolan PO, Balota DA, Roediger HLI. Part-set cuing effects in younger and older adults. Psychol Aging 2004; 19: Mendonsa G, Dobrowolska J, Lin A, Vijairania P, Jong YJ, Baenziger NL. Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts. PLoS ONE 2009; 4:e4655 PMC Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat Neurosci 2009; 12: Miller MI, Qiu A. The emerging discipline of Computational Functional Anatomy. Neuroimage 2009; 45:S16-S Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L, Kaleem M, Leung D, Bryden L, Nath P, Zismann VL, Joshipura K, Huentelman MJ, Hu-Lince D, Coon KD, Craig DW, Pearson JV, Holmans P, Heward CB, Reiman EM, Stephan D, Hardy J. A survey of genetic human cortical gene expression. Nat Genet 2007; 39: Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, for the Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352: Price JL. What does it take to stay healthy past 100?: Commentary on "No disease in the brain of a 115- year-old woman". Neurobiol Aging 2008; 29: Qiu A, Younes L, Miller MI, Csernansky JG. Parallel transport in diffeomorphisms distinguishes the timedependent pattern of hippocampal surface deformation due to healthy aging and the dementia of the Alzheimer's type. Neuroimage 2008; 40: Ratnanather JT, Wang L, Nebel MB, Hosakere M, Han X, Csernansky JG, Miller MI. Validation of semiautomated methods for quantifying cingulate cortical metrics in schizophrenia. Psychiatry Research Neuroimaging 2004; 132: Ray M, Zhang W. Integrating genetic and phenotypic information to analyze Alzheimer's disease. J Alz Dis 2009; 16: Ray M, Ruan J, Zhang W. Variations in the transcriptome of Alzheimer's disease reveal modular networks involved in cardiovascular diseases. Genome Biology 2008; 9:R Ruhkin A, Vaillant M, Qui A, Younes L, Ratnanather JT. Analysis of hippocampal shape change over time in a study of Alzheimer's disease based on mementa of the EPDiff equation of computational anatomy. Effective computational methods for highly oscililatory problems: the interplay between mathematical theory and applications Cambridge, UK, Isaac Newton Institute of Mathematical Sciences. Ref Type: Report 79. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 2007; 13: Salat DH, Greve DN, Pacheco JL, Quinn BT, Helmer KG, Buckner RL, Fischl B. Regional white matter volume differences in nondemented aging and Alzheimer's disease. Neuroimage 2009; 44: Samanez-Larkin GR, D'Esposito M. Group comparisons: Imaging the aging brain. Social Cognitive and Affective Neuroscience 2008; 3: PMC Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML, MK-677 Protocol 30 Study Group (includes Galvin JE. Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial. Neurology 2008; 71: Page 33

34 83. Shannon BJ, Buckner RL. Functional-anatomic correlates of memory retrieval that suggest nontraditional processing roles for multiple distinct regions within posterior parietal cortex. J Neurosci 2004; 24: Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark C.M., Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VMY, Trojanowski JQ, and the Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 2009; 65:DOI: /ana Thirumangalakudi L, Yin L, Vittal-Rao H, Grammas P. IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons. J Alz Dis 2007; 11: Tse C-S, Balota DA, Moynan SC, Duchek DA, Jacoby LL. The utility of placing recollection in opposition to familiarity in early discrimination of healthy aging and very mild dementia of the Alzheimer's type (DAT). Neuropsychology. 2009;(In Press) 87. Van Essen DC. A population-average, landmark- and surface-based (PALS) atlas of human cerebral cortex. Neuroimage 2005; 28: Velanova K, Lustig C, Jacoby LL, Buckner RL. Evidence for frontally mediated controlled processing differences in older adults. Cereb Cortex 2007; 17: Velez-Pardo C, Arellano JI, Cardona-Gomez P, Jimenez Del Rio M, Lopera F, DeFelipe J. CA1 hippocampal neuronal loss in familial Alzheimer's disease presenilin-1 E280A mutation is related to epilepsy. Epilepsia 2004; 45: Vincent JL, Snyder AZ, Fox MD, Shannon BJ, Andrews JR, Raichle ME, Buckner RL. Coherent spontaneous activity identifies a hippocampal-parietal memory network. J Neurophysiol 2006; 96: Wijsman EM, Daw EW, Yu C-E, Payami H, Steinbart EJ, Nochlin D, Conlon EM, Bird TD, Schellenberg GD. Evidence for a novel late-onset Alzheimer disease locus on chromosome 19P13.2. Am J Hum Genet 2004; 75: Yap MJ, Balota DA. Additive and interactive effects on response time distributions in visual word recognition. J Exp Psychol Learn Mem Cogn 2007; 33: Yap MJ, Balota DA, Cortese MJ, Watson JM. Single versus dual process models of lexical decision performance: insights from RT distributional analysis. J Exp Psychol Hum Perceptions Performance 2006; 32: Yu P, Grant PE, Qi Y, Han X, Segonne F, Pienaar R, Busa E, Pacheco J, Makris N, Buckner RL, Golland P, Fischl B. Cortical surface shape analysis based on spherical wavelets. IEEE Trans Med Imaging 2007; 26: Zacks JM, Swallow KM. Event segmentation. Psychol Sci 2007; 16: Zacks JM, Speer NK, Vettel JM, Jacoby LL. Event understanding and memory in healthy aging and dementia of the Alzheimer type. Psychol Aging 2006; 21: Zhang R, Hu X, Khant H, Ludtke SJ, Chiu W, Schmid MF, Frieden C, Lee J-M. Interprotofilament interactions between Alzheimer's AΒ1-42 peptides in amyloid fibrils revealed by cryo-em. Proc Natl Acad Sci ; 106: List 3: publications authored by Center investigators but not directly using Center resources, n= Alzheimer's Association National Board of Directors. Research consent for cognitively impaired adults: Recommendations for Institutional Review Boards and Investigators. ADAD 2004; 18: Andrieu S, Coley N, Aisen PS, Carrillo M, DeKosky S, Durga J, Fillit H, Frisoni GB, Froelich L, Gauthier S, Jones R, Jonsson L, Khachaturian Z, Morris JC, Orgogozo JM, Ousset PJ, Robert P, Salmon E, Sampalo C, Verhey F, Wilcock G, Vellas B. Methodological issues in primary prevention trials for neurodegerative dementia. J Alz Dis 2009; 16: Armstong RA, Cairns NJ. Spatial patterns of the pathological changes in neuronal intermediate filament inclusion disease (NIFID): an a-internexin immunohistochemical study. J Neural Transm 2007; 114: Armstrong RA, Lantos PL, Cairns NJ. Overlap between neurodegenerative disorders. Neuropathology 2005; 25: Page 34

35 5. Armstrong RA, Lantos PL, Cairns NJ. What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease? Neuropathology 2008; 28: Bacon D, Fisher RS, Morris JC, Rizzo M, Spanaki MV. American Academy of Neurology position statement on physician reporting of medical conditions that may affect driving competence. Neurology 2007; 68: Bateman RJ, Klunk WE. Measuring target effect of proposed disease-modifying therapies in Alzheimer's disease. Neurotherapeutics 2008; 5: Bateman RJ, Eidelberg D. Testing a test for Alzheimer disease. Neurology 2007; 68: Beekly DL, Ramos EM, Lee WW, Deitrich WD, Jacka ME, Hubbard JL, Koepsell TD, Morris JC, Kukall WA, the Alzheimer's Disease Centers. The National Alzheimer's Coordinating Center (NACC) Database: The Uniform Data Set. Alz Dis Assoc Disord 2007; 21: Behrens MI, Lendon C, Roe CM. A common biological mechanism in cancer and Alzheimer's disease? Curr Alzheimer Res. 2009;(In Press) 11. Brown LB, Ott BR, Papandonatos GD, Sui Y, Ready RE, Morris J.C. Prediction of on-road driving performance in patients with early Alzheimer's disease. J Am Geriatr Soc 2005; 53: Burke WJ, Kumar VB, Pandey N, Panneton WM, Gan Q, Franko MW, O'Dell M, Li SW, Pan Y, Chung HD, Galvin JE. Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathol 2008; 115: Cairns NJ, Grossman M, Arnold SE, Burn DJ, Jaros E, Perry RH, Duyckaerts C, Stankoff B, Pillon B, Skullerud K, Cruz-Sanchez FF, Bigio EH, Mackenzie IRA, Gearing M, Juncos JL, Glass JD, Yokoo H, Nakazato Y, Mosaheb S, Thorpe JR, Uryu K, Lee VMY, Trojanowski JQ. Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 2004; 63: Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL, III, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114: Carr DB, Flood K, Steger-May K, Schechtman KB, Binder E. Characteristics of frail older adults drivers. J Am Geriatr Soc 2006; 54: Carr DB, Meuser TM, Morris JC. Driving retirement: the role of the physician. CMAJ 2006; 175:601 PMC Carr DB, Duchek JM, Meuser TM, Morris JC. The older driver with cognitive impairment. American Family Physician 2006; 73: Carr DB. The role of Emergency Physicians in older driver safety. Ann Emerg Med 2004; 43: Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model. J Clin Invest 2005; 115: PMC Cirrito JR, Holtzman DM. Synaptic activity, amyloid-β and Alzheimer's disease. In: Jucker M, Beyreuther K, Haass C, Nitsch R, Christen Y, editors. Alzheimer: 100 Years and Beyond, Research and Perspectives in Alzheimer's Disease. Heidelberg: Springer-Verlag Berlin Heidelberg, 2006: Coats MA, Morris JC. Antecedent biomarkers of Alzheimer's disease: The Adult Children Study. J Geriatr Psychiatry Neurol 2005; 18: D'Angelo G, Weissfeld L, GenIMS Investigators. An index approach for the Cox model with left censored covariates. Stat Med 2008; 27: Dahl LJ, Wright S, Xiao S, Keeven A, Carr DB. Quality improvement in long term care: the Psychotropic Assessment Tool (PAT). J Am Med Dir Assoc 2008; 9: Fagan AM, Christopher E, Taylor JW, Parsadanian M, Spinner M, Watson M, Fryer JD, Wahrle S, Bales KR, Paul SM, Holtzman DM. ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol 2004; 165: PMC Page 35

36 25. Fagan AM, Csernansky CA, Morris JC, Holtzman DM. The search for antecedent biomarkers of Alzheimer's disease. Journal of Alzheimer's Disease 2005; 8: Fillenbaum CG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer K, Heyman A. Consortium to establish a registry for Alzheimer's disease (CERAD): The first tweny years. Alzheimer's & Dementia 2008; 4: Galvin JE, Scharff DP, Glasheen C, Fu Q. Development of a population-based questionnaire to explore psychosocial determinants of screening for memory loss and Alzheimer Disease. Alzheimer Dis Assoc Disord 2006; 20: Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J. Effects of Galantamine on measures of attention: results from 2 clinical trails in Alzheimer disease patients with comparisons to Donepezil. Alz Dis Assoc Disord 2008; 22: Galvin JE. Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra. Acta Neuropathol 2006; 112: Galvin JE. Pass the grain; spare the brain. Neurology 2007; 69: Galvin JE, Fu Q, Nguyen JT, Glasheen C, Scharff DP. Psychosocial determinants of intention to screen for Alzheimer's disease. Alzheimers Dement 2008; 4: Galvin JE, Palamand D, Strider J, Milone M, Pestronk A. The muscle protein dysferlin accumulates in the Alzheimer brain. Acta Neuropathol 2006; 112: PMC Gao F, Xiong C, Yan Y, Yu K, Zhang Z. Estimating optimum linear combination of multiple correlated diagnostic tests at a fixed specificity with Receiver Operating Characteristic Curves. J Data Sci 2008; 6: Hogue CW, Fucetola R, Hershey T, Freedland K, Davila-Roman VG, Goate AM, Thompson RE. Risk factors for neurocognitive dysfunction after cardiac surgery in postmenopausal women. Ann Thorac Surg 2008; 86: Homma A, Meguro K, Dominguez J, Sahadevan S, Wang YH, Morris JC. Clinical dementia rating workshop: the Asian experience. Alzheimer Dis Assoc Disord 2006; 20: Ince PG, Morris JC. Demystifying lobar degenerations; tauopathies vs. gehrigopathies. Neurology 2006; 66: Jarvik L, LaRue A, Blacker D, Gatz M, Kawas C, McArdle JJ, Morris JC, Mortimer JA, Ringman JM, Ercoli L, Freimer N, Gokhman I, Manley JJ, Plassman BL, Rasgon N, Roberts JS, Sunderland T, Swan GE, Wolf PA, Zonderman AB. Children of persons with Alzheimer disease: What does the future hold? Alz Dis Assoc Disord 2008; 22: Lippa CF, Morris JC. Alzheimer neuropathology in nondemented aging; keeping mind over matter. Neurology 2006; 66: MacLean K, Berg-Weger M, Meuser TM, Carr D. Driving retirement: Help with counseling older patients. Famliy Practice Recertification 2007; 29: Meuser TM, Carr DB, Ulfarsson GF. Motor-vehicle crash history and licensing outcomes for older drivers reported as medically impaired in Missouri. Accid Anal Prev 2009; 41: Morris JC. Dementia update Alzheimer Dis Assoc Disord 2005; 19: Morris JC, Cummings J. Mild cognitive impairment (MCI) represents early-stage Alzheimer's disease. Journal of Alzheimer's Disease 2005; 7: Morris JC. Mild cognitive impairment is early-stage Alzheimer disease; time to revise diagnostic criteria. Arch Neurol 2006; 63: Morris JC, Quaid KA, Holtzman DM, Kantarci K, Kaye J, Reiman EM, Klunk WE, Siemers ER. The role of biomarkers in studies of presymptomatic Alzheimer's disease. Alzheimer's & Dementia 2005; 1: Morris JC, Weintraub S, Chui HC, Cummings J, DeCarli C, Ferris S, Foster NL, Galasko D, Graff-Radford NR, Peskind ER, Beekly D, Ramos EM, Kukull WA. The Uniform Data Set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer Disease Centers. Alz Dis Assoc Disord 2006; 20: Morris JC, Cummings JL. Workshop reports from the Third Asia-Pacific Regional Meeting of the International Working Group on harmonization of dementia drug guidelines. ADAD 2006; 20: Ott BR, Heindel W, Papandonatos GD, Festa EK, Davis JD, Daiello LA, Morris JC. A longitudinal study of drivers with Alzheimer's disease. Neurology 2008; 70: Page 36

37 48. Ott BR, Anthony D, Papandonatos GD, D'Abreu A, Burock J, Curtin A, Wu C-K, Morris JC. Clinician assessment of the driving competence of patients with dementia. J Am Geriatr Soc 2005; 53: Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol 2005; 62: Rapoport MJ, Herrmann N, Molnar F, Rochon PA, Juurlink DN, Zagorski B, Seitz D, Morris JC, Redelmeier DA. Psychotropic medications and motor vehicle collisions in patients with dementia. J Am Geriatr Soc 2008; 56: Schneider LS, Clark CM, Doody R, Ferris SH, Morris JC, Raman R, Reisberg B, Schmitt FA. ADCS Prevention Instrument Project: ADCS-clinicians' global impression of change scales (ADCS- CGIC), self-rated and study partner-rated versions. Alzheimer Dis Assoc Disord 2006; 20:S124- S Schneider LS, Raman R, Schmitt FA, Doody R, Insel P, Clark CM, Morris JC, Reisberg B, Petersen RC, Ferris SH. Characteristics and performance of a modified version of the ADCS-CGIC+ for mild cognitive impairment clinical trials. Alz Dis Assoc Disord 2009; 53. St.George-Hyslop PH, Morris JC. Will anti-amyloid therapies work for Alzheimer's disease? The Lancet 2008; 372: Steffens DC, Otey E, Alexopoulos GS, Butters MA, Cuthbert B, Ganguli M, Geda YE, Hendrie HC, Krishnan RR, Kumar A, Lopez OL, Lyketsos CG, Mast BT, Morris JC, Norton MC, Peavy GM, Petersen RC, Reynolds CF, Salloway S, Welsh-Bohmer KA, Yesavage J. Perspectives on depression, mild cognitive impairment, and cognitive decline. Arch Gen Psychiatry 2006; 63: Wang CL, Carr D. Older driver safety: A report from the Older Drivers Project. J Am Geriatr Soc 2004; 52: Wilkins CH, Moylan K, Carr D. Diagnosis and management of dementia in long-term care. Annals of Long Term Care: Clinical Care and Aging 2005; 13: Wippold FJ, Cairns N, Vo K, Holtzman DM, Morris JC. Neuropathology for the neuroradiologist: plaques and tangles. AJNR Am J Neuroradiol 2008; 29: PROTECTION OF HUMAN SUBJECTS S E E CLINIC AL COR E 8. INCLUS ION OF WOME N AND MINOR ITIE S S E E CLINIC AL COR E 9. TAR GE TE D/PLANNE D E NR OLLMENT TABLE S E E CLINIC AL COR E 10. INCLUS ION OF CHILDR E N NOT APPLICABLE 11. VERTEBRATE ANIMALS NOT APPLICABLE 12. SELECT AGENTS NOT APPLICABLE 13. MULTIPLE PD/PI LEADERSHIP PLAN NOT APPLICABLE 14. CONS ORTIUM/CONTRACTUAL ARR ANGE ME NTS SEE RESPECITVE CORES 15. LETTERS OF SUPPORT/CONS ULTANTS Mark S. Wrighton, Chancellor of Was hington Univers ity Larry S. Shapiro, Dean, Was hington Univers ity S chool of Medicine J oan D Ambrose, E xecutive Director, Alzheimer s Association, St. Louis Chapter Page 37

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40 16. RESOURCE SHARING PLAN(S )- SEE CORE A: ADMINISTRATION Page 40

41 Overview Morris, John C. Table 1. Federal Funded Grants Supported by Resources of Washington University ADRC Year Since Last Competing Renewal Submission Principal Source & Project Investigator/ Grant Title/Number Role of ADC Amount Period Project Director Abrams, Richard Balota, DA Bateman, Randyl Buckner, Randy Buckner, Randy L. Buckner, Randy L. Buckles, Virginia Burns, Jeffrey Burton, Harold Cairns, Nigel Cairns, Nigel Csernansky, John Csernansky, John Csernansky, John Dickerson, Brad Mass Gen Hospital Eye movements during visual search in healthy aging and very mild DAT P50AG05681, Pilot 23.1 Attention profiles in healthy aging and early stage DAT, 5 P01 AG03991, Project 3 Paul Beeson Award in Aging: Aβ and proteomic analysis of CSF in AD and aging K23AG Healthy Aging and Senile Dementia Neuroimaging Core 5 P50 AG03991 Structure and Cognition (LifeSpanII) RO1 AG021910/HHMI Functional Anatomic Characterization of Memory Difficulties Using MRI 5 P50 AG05681, Project 4 Informed Consent in Demented Individuals, AG05681 Extrapyramidal Signs in Alzheimer Disease 2 T32 NS07205 Braille reading and adaptive plasticity in the human brain Determination of fibril size in inclusions of FTLD-U U01 AG TDP-43 Proteinopathy: Discovering Causes of Clinical and Neuropathological Heterogeneity U01-AG16976 Cortciolimbic degeneration and treatment response of dementia R01 MH60883 Predicting cognitive decline in nondemented elder subjects, P01AG03991, Project 4 Stress, Glucocoriciods and Alzheimer Disease 1R01AG Explorations of distinct effects of aging and AD on Hippocampus $35,000 $660,053 NIH NIH- /HHMI $1,025,00 0 (direct) $683,548 NIH training grant $113,480 NINDS $2,314,26 9 NACC $51,000 NACC/NI A/NIH $30,000 NIH 1,416,424 NIH $680,602 $1,400,00 0 NIH $205,556 5/1/06-4/30/07 1/1/04-12/31/08 09/01/ /31/2011 1/1/ /08 3/1/2005 2/28/2005-5/1/00-4/30/05 5/1/03-4/30/05-7/1/02-6/30/ /1/2005-6/30/2007 1/1/ /31/ /1/ /30/2010-1/1/04-12/31/08 9/29/2005-9/28/2010 9/30/04-5/31/07 41 Subjects 424 Subjects ApoE & data 11 Subjects 168 subjects 8 Subjects 10 subjects 83 Subjects 213 scans and data 10 fmri scans 6 Tissue 7 Tissue 246 subjects 99 subjects 39 Subjects 150 MRI scans Page 41

42 Overview Morris, John C. Fagan, Anne Antecedent Biomarkers for AD; the / Adult Children Study/Project 2: CSF 10/01/05 $133,000 Biomarkers of Antecedent AD/1 P01 9/30/10 per yr AG ApoEs Fagan, Anne. Fagan, Anne Head, Denise Fischl, Bruce Harvard Med School Galvin, James E. Galvin, James E. Galvin, James E. Gambetti, P Case Western Reserve Univ. Gandy, Samuel Mt. Sinai Med Sch. Gandy, Samuel Mt. Sinai Med. Sch. Gazzaniga, Michael UC Santa Barbara Geschwind, Daniel UC Los Angeles Goate, Alison Goate, Alison Goate, Alison Novel biomarkers to predict Alzheimer s disease, Project 2, Adult Children Study P01 AG Levels of CSF Biomarkers and structural neuroimaging measures, Project 2 P01AG03991 Automated analysis of healthy and diseased brain tissue 1 R01 RR A multicenter, randomized, doubleblind, placebo-controlled trial of simvastatin to slow the progression of Alzheimer s disease, U01AG10483 PIB Imaging In Lewy Body Disease pending Dementia of the Parkinson type: Clinicopathologic phenotype K08 AG20764 Pathogenetic mechanism of prion diseases AG14359 Interdisciplinary Approach to Alzheimer Drug Discovery AG10491 CSF Alcadein Fragment Pattern as a Biomarker for AD AG23611 National FMRI Data Center Sequencing of FTD candidate gene R01AG Functional studies of variants in the muscarinic acetylcholine receptor M2 (CHRM2) that demonstrate association with alcohol dependence, depression and related phenotypes 5U10AA Genomic search for susceptibililty to Alzheimer s disease AG Identification of Genes that Modify Age of Onset of AD, 5P50 AG05681; Project 1 $642,046 $105,899/ yr NIH $250,000 yearly, ADCS NACC/ $50,000 $455,538 NIH/ $1,000,00 0 NIH 6,800,000 1,200,000 NSF (also NIH) $4,682,26 0 NIH/ $2,653,34 8 1/1/04-12/31/ /1/02-7/31/06 7/1/03-6/30/05 7/1/2007-6/30/2009 4/1/02-3/31/05 6/15/2002-5/31/2007 7/1/2005-6/30/2010 6/1/2006-5/31/ /01/99-9/30/04 9/1/2005 6/30/2010 AA 9/1/1989-8/31/2009 NIH $1,892,933 NIH $560,025 09/ /2008 5/1/00-4/30/05 24 subjects 33 APOe 98 MRI Scans And data 270 MRI Scans 6 Subjects 16 Subjects 67 tissue samples 18 Tissue 60 ApoEs 12 Tissue 44Tissue 270 MRI Scans 3 Tissue 50 Tissue brain 2652 DNA Data 385 subjects Page 42

43 Overview Morris, John C. 802 data, / Goate A./Mayeux, LOAD Genetics initiative/ 9/1/05- blood and $200,000 R. Columbia U 1U24AG /31/10 autopsy-332 per yr subjects Goate, Alison Grammas, Paula Texas Tech. Univ. Hagen, Jody U of Arkansas Medical School Hardy, John Hardy, Peter Univ. Kentucky Head, Denise Holtzman, David M. Holtzman, David M.. Holtzman, David M. Holtzman, David M. Hu, H Johnson, David K. Kauwe, John Kramer, Patti Oregon Health Sciences Univ. Larsen, Randy National Cell Repository for Alzheimer s Disease Is there a Link between Alzheimer s and Atherosclerosis R01AG Severity & Progression of AD in African Americans & Caucasians Expression studies examining novel loci involved in genetic susceptibility to neurologic disease Pseudo T2 image for correlations between T2 changes & clinical status Structure and Cognition (LifeSpanII) RO1 AG021910/HHMI Assessment of apoe isoform level by mass spectrometry AG13956 and AG03991 CNS Apolipoprotein J in Aβ deposition5 P50 AG05681, Project 2 Novel biomarkers to predict Alzheimer s disease, Project 2 P01 AG03991 Probing for antecedent biomarkers of AD by proteomics. R21 AG Biomarker for alzheimer's disease NIH F32 AG A1 Weight loss in dementia P50AG05681 Evaluating SNPs that are associated with Late-onset Alzheimer's disease for their contribution to variance in age at onset in familial AD cases AG16208 Genetic Associations with Alzheimerfree Survival R01 AG Emotional Aging: Preservation of Function in the Elderly and Alzheimer's Patients R01AG NIH $1,163,609 5/1/03-4/30/05 11/1/04-10/31/09 6/1/03-5/30/04 Intramural NIH submission 2008 NIH- /HHMI $1,025,00 0 (direct) NIH $1,500, ,002 $642, tissue and data 11 tissue samples 37 data subjects 3/1/2005-2/28/2006 8/1/2004-7/31/2009 5/1/01-4/30/05 1/1/04-12/31/08 9/30/04 9/29/06 NIH 7/1/2005-6/30/2008 $320,000 NIH $2,017,46 9 $38,250 $934,877 7/1/2004 6/30/2005 4/1/2003-8/31/2008 9/15/2005-6/30/2009 5/15/07-3/31/12 Phantom scanned 3 Subjects 10 Tissue 21 Subjects 98 subjects And ApoE 39 CSF samples for pilot data 92 Tissue CSF 4 Tissue hippocampal and temporal cortex tissue 440 Data Only 129 subjects Data Only 59 Tissue DNA or frozen brain tissue 16 Subjects Page 43

44 Overview Morris, John C. Lee, Jin-Moo Matrix metalloproteinases and NIH Alzheimer's Disease 1,125,000 R01 NS Tissue Liscic, Rajka Croatia McDaniel, M Menon, Vinod Stanford Univ. Mintun, Mark Mintun, Mark Mintun, Mark Montine, Thomas Univ. Washington Morris, John C. Morris, John C. Morris, John C. Morris, John C. Morris, John C. Morris, John C Morris, John C. Morris, John C Mucke, Lennart Mukherjee, Odity Cognitive Profiles of Early Onset FTD and DAT (CDR 0.5): Isolating Distinguishing Features P01AG03991 Aging and Prospective Memory: A Multiprocess Analysis P50AG05681, Pilot 22.3 Longitudinal fmri study of cognitive development K25 HD Amyloid Imaging in the Adult Children Study P01AG Amyloid Imaging to Evaluate Risk in AD. P01AG05681 HASD Neuroimaging Core, CAPs P01AG03991 Alzheimer's Disease Genetics Consortium Alzheimer s Disease Neuroimaging Initiative, U01 AG Alzheimer's Disease Cooperative Study U01AG10483 (See also Table 3) Alzheimer's Disease Neuroimaging Initiative U01AG10483 Antecedent biomarkers for AD: The Adult Children Study, P01AG Assessment measures for AD primary prevention trials U01AG10483 Autopsy Program Satisfaction in the Memory and Aging Project P50ag05681 Center for Aging K07 AG Healthy Aging and Senile Dementia P01AG03991 Molecular markers for Alzheimer disease cognitive impairment P50 AG Reducing the candidate region on 17q21 in the HDDD2 kindred Fogarty Fellowship $120,000 $35,000 NIMH NIH $1,120,00 0 $726,800 $650, ,000 1/1/ /31/2008 5/1/05-4/30/06 4/16/01-3/3106 7/1/2005-6/30/2010 5/1/2005-4/30/2010 1/1/04-12/31/08 18 subjects 5 data only 51Subjects ApoE 270 MRI Scans 200 Subjects 67 Subjects 107 Subjects 44 Tissue 6/1/05-9/1/09 29 subjects NIH 7/1/05 6/30/10 NIH 9/30/04-8/31/08 $235,000 ADCS - NIH $2,499, $535,000 $6,156,47 4 NIH 6,143,429 NIH 9/30/05-6/30/10 29 Subjects 19 Subjects 17 ApoE genotypes 1/1/02-1/1/07 32 subjects 5/1/2007-5/30/2008 7/1/02-6/30/07 1/1/04-12/31/08 5/15/2004 3/31/2009 7/1/2005-6/30/ Subjects Adm. resources 112 DNA (9) from brain, ApoE, store biofluids 4 Tissue Provided DNA - 19 subjects Page 44

45 Overview Morris, John C. Is allele specific expression a risk Nowotny, Petra factor for late-onset Alzheimer's NIH 7/1/2003- disease? $878,121 6/30/ Tissue AG Powers, William Zazulia, Allyson Richard Perrin Rohrbaugh, John Rosen, Bruce UCLA Shaw, Les M ADNI, Univ. Pennsylvania Sheline, Yvette Small, Brent Univ S. Florida Stephan, D/ Reiman, E. Translational Genomics/Arizoan State Univ. Sweet, R. U. Pittsburgh Thomas, Ayanna Van Deerlin, Vivianna Univ. Pennsylvania Wells, William Harvard Med. Sch. Wilkins, Consuelo Cerebral Vascular and Metabolic Mechanisms in Alzheimer s Disease AG ApoE4 antibody titration B Falling and Alzheimer s disease: Cognitive factors Center for Functional Imaging Technologies Regional Resource for functional brain imaging. 5P41 RR Validation of a multiplex immunoassay for CSF Biomarkers U01-AG Treatment Outcome Of Vascular Depression MH A1 Changes in Cognitive Performance in Preclinical AD: A Collaborative Analysis U01AG16976 Neurogenomics of Alzheimer's Disease and Aging R01 AG Psychosis of Alzheimer s Disease U01 AG16976 Metamemory Deficits in Alzheimer's Disease AG Genome wide association study of frontotemporal dementia +/- motor neuron disease with TDP-43 pathology or progranuli mutations AG17586 Statistical Atlas of Cortex and White Matter Anatomy, P41RR31218 (PI R. Kikinis) Vitamin D in Older Adults: Cognition, Mood, and Hippocampal Volume 1K23AG A1 NIH 1,912,500 T32- Dave Holtzman $500,000 $28,750 NCRR $818,323 yearly 4/1/2005 3/31/ / /2009 5/1/02-4/30/03 extended 9/28/99-8/31/04 21 subjects 4 Tissue 4 subjects 270 MRI Scans 9/1/ Tissue NIMH 1,940,480 /NAC C $25,000 $28,695, NACC $7,580 $110,000 NIH 853,000 NIH - Beeson Career Dev. $827,037 7/1/2000-6/30/2005 7/1/08-6/30/09 10/1/03-9/30/08 7/1/02-6/30/04 extended 7/1/2004-6/1/2006 3/1/2005-2/28/2010 5/1/04-4/30/09 9/15/2006-6/30/ subjects 586 Data 5 Tissue samples 58 subjects 47 tissue samples 57 subjects 9 Tissue 75 MRI scans and data 111 Subjects Page 45

46 Overview Morris, John C. Vitamin D deficiency in normal aging and AD NIH 7/1/03-3 tissue Willkins, Consuelo BIRCWH Scholar s Award, K12 BIRCWH 6/30/05 samples HD01459 Williams, Monique Xiong, Chengjie Zacks, Jeffrey. Zacks, Jeffrey Vascular Risk Factors in Alzheimer Disease 1K12RR Statistics in AD Publications K25AG Event perception across the life-span P50AG05681, Pilot 20.2 Neural Architecture of Event Comprehension, R01MH NIH, NCRR $67,875 $351,608 $26,750 NIH $669,420 9/17/2007-6/30/2008 9/1/05-6/30/08 5/1/03-4/30/04 1/1/04-12/31/ Data Only 111 genotypes and subject data 10 subjects 40 subjects Page 46

47 Overview Morris, John C.. Table 2. Non-Federal (e.g. Foundation) Funding Supported by Resources of the Washington University ADRC Year Since Last Competing Renewal Submission Principal Investigator/ Project Director Abraham, Carmela Avidan, Michael Bakal, D. Calgary Health Region-Canada Balota, D. Duchek, J. Head, D. Jackson, J. Bateman, Randall Bateman, Randall Bateman, Randall Bateman, Randall Bateman, Randall Beg, M.F. Simon Fraser Univ. Buckner, Randy L. Buckner, Randy L. Grant Title/Number The function of Klotho in the normal and aging brain Cognitive dysfunction following surgery and major illness Adapting the CDR for Palm Pilot administration Structural Studies of Personality and Cognition in Aging and Early Stage Alzheimer s Disease. Familial Adult Children Study Assessment of LY mediated inhibition of A-Beta formation determined by Leucine in Healthy subjects/n/a Resting Brain Metabolism in the Familial Adult Child Study CSF Tau IP-MS n/a Human CNS Apoliproprotein E Isoform Production and Clearance A Improving Sensitivity of Early Detection of AD via Multidimensional Analysis of Longitudinal MRI Scans. Volume Decline Associated with Socioeconomic Privilege: Structural Neuroimaging in Older Adults Exploring network disruption in aging independent of AD Source & Amount Anonymous $250,000 Washington University Calgary Health Region-Canada Internal support Barnes-Jewish Hospital Foundation $100,000 Project Period 6/1/2006-5/31/2008 9/1/04-8/31/06 7/2004 NA 2/1/05-1/31/07 Eli Lilly/$721,882 5/1/2006 for 2 nd phase 12/31/2007 McDonnell Foundation Dept Neurology American Health Assistance Foundation $150,000 Pacific Alzheimer Research Foundation (Canada) $80,000/year Howard Hughes Medical Institute Howard Hughes Medical Institute $5,500,000 3/30/2008-3/30/ / / / / NA Role of ADC 20 Tissue 643 data only Data on 58 Subjects 100 MRI scans, psychomet ric and clinical data Recruit 6 ADRC kindreds to participate 18 subjects 24 APOE genotypes 6 Subjects 33 Tissue 5 Subjects 188 MRI scans and clinical status 371 data only 43 data Page 47

48 Overview Buckner, Randy L./ Head, Denise Buckner, Randy, L. Buckner, Randy, L. Cairns, Nigel J Carr, David Storandt, Martha Carr, David Chapman, Sandra Univ. Texas SW Csernansky, John Dale, Anders UC San Diegl Deanne, Rashid Rochester Univ. Demattos, Ronald Eli Lilly & Co. Dickerson, Brad Harvard Med Sch. Measures of Cognition Cognitive Neuroscience of Human Memory 99-63/ The Central Neuroimaging Data Archive: A resource for coordinating, maintaining, and exploring neuroimaging data N Role of valosin-containing protein in neuron death and frontotemporal dementia Howard Hughes Medical Inst. 2,500,000 James S. McDonnell Foundation $300,000 McDonnell Center for Higher Brain Function $80,000 The Hope Center for Neurological Disorders, the Buchanan Fund (ADRC gfit), and the Barnes- Jewish Hospital Foundation 9/1/2000-9/1/ /1/99-12/1/06 7/1/03-6/30/05 N/A Driving and AD Internal support 2005 Fitness to Driver in Neurologically Impaired Older Adults Pending Discourse in Hereditary Dysphasic Dementia N/A Correlation of plasma corticsol and clinical progression in early DAT ADNI Pilot slrp levels in plasma of Alzheimer s disease and control subjects/ N/A To study the protein profile differences between Alzheimer s disease patients and non-ad age-matched controls. Genetic influences on cortical thickness: Modulation of thickness in AD-vulnerable brain regions vs. agesusceptible brain regions Missouri Department Transportation $100,000 Frank R. Garrott Research Fund/$75,000 Washington University Howard Hughes Medical Institute Internal support Eli Lilly and Company Internal support 10/1/2007-9/1/ /1/2001 9/30/ N/A 12/17/ /31/2005 NA Morris, John C MRI scans 85 MRI Scans 110 MRI Scans Extract 8 DNA sequence on genotypes Maintain 3 cell lines 201 data only 3 data 11 subjects 23 blood samples 93 MRI scans 116 Plasma (2 longitudinal samples for 58 subjects) 1 CSF 60 tissue 67 ApoE & scans Page 48

49 Overview Dickerson, Brad Harvard Med Sch. Fagan, Anne Funck, Theo TF Instruments Germany Galvin, James E. Galvin, James E. Galvin, James E. Galvin, James E. Galvin, James E. Galvin, James E. Gao, Zhiyong Siemens BDNF/ exploratory work Internal support N/A Misdiagnosis study: Comparing PIB status with Discordant Clinical Diagnoses Diagnostics of Neurodegenerative Disorders by Ultrasonic Investigations Exploring psychosocial determinants of intention to screen for memory loss In vitro & in vivo models of synucleinopathies Key features inventory: Early diagnosis of dementia to improve quality of life # Evaluation of the AD8 as a self-rating tool Relationship of Frailty to Longitudinal Cognitive Performance Key features inventory: Early diagnosis of dementia to improve quality of life in dementia clinic Study of Alzheimer s disease using in vitro methods Internal support NA TF Instruments 2005 Alzheimer s Association $240,000 American Federation for Aging Research, Beeson Award $450,000 Longer life Foundation $45,851 Internal support 2005 Internal support Longer life Foundation $45,851 Siemens $500,000 8/1/2003-7/30/2006 7/1/02-6/30/05 10/1/03-10/31/ /1/03-10/31/ /1/07-9/30/12 Morris, John C.. 67 Assess availability and provide genotypes 79 Data only 50 tissue CSF Staff support 97 tissue samples 117 subjects 740 subjects 417 subjects data 255 subjects 500g brain tissue Gitcho, Michael TDP-43 gene expression Internal support NA 3 Tissue Goate, Alison Goate, Alison Goate, Alison Discovery of causative gene underlying Frontotemporal Dementia with ubiquitinepositive neuronal inclusions on chromosome 17 Pittsburgh compound B: A quantitative endophenotype for genetic studies of AD risk?/n/a Variation in tau expression and risk for PSP N/A WU Genome Sequencing Center $50,000 Anonymous Foundation/ $250,000 Barens Jewish Foundation $90,000 8/1/2005 7/31/2006 1/1/ /31/2007 7/1/2006-6/30/ tissue Process DNA/ provide APOe: 119 samples. 6 Tissue frozen brain Page 49

50 Overview Golland, P. Massachusetts General Hosp., MIT Graff, Caroline Karolinska Inst. Grant, Betsy Grupe, Andrew Celera Diagnostics Grupe, Andrew Celera Diagnostics Han, X. Harper, Patrick Head, D. Mintun, M. Head, D. Balota, D. Goate, A. Jackson, J Head, D./Bugg, J. Head, D./Bugg. J. Head, Denise Predictive Modeling in Image- Based Studies of Anatomical Shape and Function Faculty Startup funds, EECS Department, MIT MIT $75K and 4 RA PS1 Fibroblast cell lines/n/a Internal support N/A Motivation of Normal Adults to participate in AD research Chromosome 10 Analyses Functional validation of genes with LOAD Comparison of CSF biomarkers The possible connection between thyroid disease treatment and subsequent Alzheimer s Disease Regional Volumes and Amyloid Deposition in Nondemented Aging and Alzheimer s Disease. Frontotemporal Dementia: Cognitive and Neural Characterization of MAPT and PGRN mutations. Effects of Lifetime Physical Activity on Brain Structure and Cognition in Nondemented Aging. Predictive Utility of Precuneus Volume in Conversion to Alzheimer s Disease Diabetes and Cognitive Decline in Nondemented Older Adults Internal support 2005 Celera Diagnostics Celera Diagnostics Shared w/merck Donald H. and Mary Jane Buchanan Fund, Barnes-Jewish Foundation $10,000 St. Louis School of Pharmacy Internal support The Association for Frontotemporal Dementias (Submitted) Internal support Internal support Internal support 11/1/03-8/31/ Morris, John C MRI Scans 6 subjects; arrange for local dermatolog ist 239 subjects Data on 916 subjects 1021 DNA and brain tissue 2/1/03-1/31/04 Funds NA NA NA NA NA NA 490 Data only 110 MRI scans, psychomet ric and clinical data 69 MRI scans for 29 FTD and 40 AD subjects for pilot data 100 MRI scans, psychomet ric and clinical data 25 MRI scans and clinical data 504 data Page 50

51 Overview Head, Denise Aging and Physical Activity Internal support NA Hecimovic, S. Holtzman, David M. James E. Galvin Karakoc, Ebru Karnik, Meghana Kauwe, John Kauwe, John K Kirchhoff, Brenda Klunk, William Univ. Pittsburgh Lach, H. Lee, Jin-Moo Lee, Jin-Moo Molecular characterization of the sites of gamma secretase cleavage of APP Effects of ABCA1 on apoe levels in the Central Nervous System Sleep disturbance in AD and DLB none Clinical, Neuropsychological and Imaging Correlates of MCI Subtypes Genetic Effects on Hippocampal Structure and Function Comparison between plasma Aβ 40/42 levels and CSF Aβ 40/42 levels/ Fellowship Use of CSF Aβ as a quantitative phenotype in AD association studies/ Fellowship Functional-Anatomic Studies of Memory and Cognition PIB binding in post mortem human brain tissue Factors influencing safety in the home care of people with dementia Cerebral Microhemorrhage in AD Cerebral Microhemorrhage in Patients with Alzheimer s Disease Daniel Weinstock Fund for Alzheimer s Disease, Barnes-Jewish Hospital Foundation $20,000 WU Genome Sequencing Center $50,000 Internal support Morris, John C.. 95 data 7/1/03-6/30/05 Funds 1/1/ /31/ / /2010 Internal support 2005 Internal support Ford Foundation/N/A Ford Foundation/N/A Howard Hughes Medical Institute University of Pittsburgh/Wash ington University Saint Louis University Beaumont Faculty Development Award $5,000 Wolff Charitable Trust Alan A. & Edith L. Wolff Charitable Trust, Washington University $26, /1/2005-8/31/2008 9/1/2005-8/31/ tissue 631 data 91 data only 64 subjects data Provide plasma 293 subjects 330 DNA 3/25/ subjects 01/ / Tissue 1/1/03-12/21/03 5 subjects subjects 5/1/03-4/30/04 10 subjects Page 51

52 Overview Lee, Jin-Moo Lee, Jin-Moo Lewis, L. Lim, Wee-Shiong Singapore Mancuso, David Marchesi, Vincent McDaniel, Mark Bugg, Julie Meuser, Thomas Meuser, Thomas Mintun, Mark Mintun, Mark Morris, JC Mukherjee, Odity Mukherjee, Odity Nowotny, P Serum or CSF marker for brain injury VLP-1 as a biomarker for neuronal death in Alzheimer s Disease Does Repetitive Mild Traumatic Brain Injury Cause Long-Term Cognitive Impairment Effect of cerebrovascular lesions on AD Calcium Independent Phospholipases A2 in Alzheimer's Disease A blood test for Alzheimer's disease none Prospective memory in DAT and ApoE genotype A structured intervention to reduce caregiver grief & emotional distress: Development and Pilot Study Dementia: An Atlas of Investigation and Diagnosis FDG PIB correlations in nondemented vs. DAT A Pilot Study of C-11 PIB Brain Uptake and Binding Antecedent Biomarkers for Alzheimer s Disease Discovery of causative gene underlying Frontotemporal Dementia with ubiquitinpositive neuronal inclusions on chromosome 17/N/A Reducing the candidate region on 17q21 in the HDDD2 kindred/n/a Association of Nicastrin with early onset AD Morris, John C.. Jack Ladenson tissue Jack Ladensen Thomas E. Brew Foundation, Washington University $26,750 Tan Tock Seng Hospital & Washington Univ. Washington University Departmental Funding Yale Dept. of Pathology Internal support MO State ADRD $7,000 Nova Professional Media WU Dept. of Radiology Internal support WU Dept of Radiology Internal support Anonymous foundation $200,000 Genome Sequencing Center/ $50,000 Barnes Jewish Foundation/ $90,000 Psychiatry, Washington University Internal support NA 23 Tissue 5/1/03-4/30/04 Funds 10/30/04-6/1/ data only 4/5/04 10 tissue 06/ / Tissue NA 21 MRI scans 2/1/03-1/31/04 16 subjects /30/2004 6/30/2005 1/1/04 12/21/06 5 sets of data 50 subjects 70 subjects 9/1/04-8/21/05 35 subjects 8/1/2005 7/3/2006 7/1/2005-6/30/2006 4/1/02-3/30/04 Provide DNA-9 subjects Provide DNA 180 subjects 1000 tissue samples Page 52

53 Overview Overkamp, Wendy Palmer, Janice Perkinson, M Pickering-Brown, Stuart Univ of Manchester, UK Rademakers, Rosa Mayo Jacksonville Reiss, Allan Stanford Univ. Roe, Catherine A survey of Older Adult Preferences for Interior Design Elements for Homelike Environment Nurse and Physician Correlation and Percent Agreement In-Home Exercise Programs for Persons with Dementia Genetic analysis of FTLD-U n/a Discovering the genetic cause of HDLS A Novel fmri Method for the Detection of Incipient Alzheimer's Disease Gamma-secretase activity as a modulator of cancer and AD risk-a genetic test of this hypothesis Morris, John C.. Internal support subjects Internal support Alzheimer's Association 99,999 University of Manchester Internal support Roe, Catherine CDR Drift Internal support NA Roe, Catherine Roe, Catherine Education, Cognitive Reserve, and PIB Memory Complaints in Individuals without Cognitive Impairment: Long-Term Outcomes of the "Worried Well" Internal support Internal support Roe, Catherine CDR Drift Internal support NA Sara Mole Univ. College London Shannon, Benjamin Sharma, Vijay Molecular genetics and biology of the neuronal ceroid lipofuscinoses N/A Brain Function, Structure, and Clinical Outcomes in Aging and Alzheimer's Disease Imaging b-amyloid Plaques in the Brain Batten Disease Support and Research Association $15,000 Internal support $40000 NA 8/1/2002-5/30/ Subjects 9 subjects 06/ / Tissue 10/1/2008 to 10/1/2009 July 1, June 30, Tissue 270 MRI Scans 7/1/04-5/30/ tissue NA NA 08/ /2008 Pacific Alzheimer s Research Foundation C06-01 Stanford University Ruth K. Broad Biomedical Research Foundation $180,000 Siteman Cancer Center Pilot grant $26,400 6/1/2007-5/31/ data 198 data 448 data 1768 data 6 Tissue 112 data Internal support tissue Page 53

54 Overview Sheline, Yyette Sheline, Yvette Shulman, Howard Snider, B Joy Functional Connectivity in Early Alzheimer s Disease. PET Amyloid Imaging in Late Life Depression Discovery of Biomarkers for Alzheimer's Disease Protein degradation systems in early Alzheimer's disease Internal support NA Morris, John C fmri scans Internal support Subjects SurroMed/ NeuroDx tissue (CSF) Internal support NA 19 Tissue Storandt, Martha MCI criteria comparison Internal support 2005 Storandt, Martha Amnart analyses Internal support data only 117 data only Storandt, Martha Word Recall Internal support 8/1/04-7/31/05 30 subjects Walsh, Dominic Univ. College Dublin Wang, Rong Mt Sinai Med. Sch. Warhle, Suzanne Wilkins, Consuelo Willliams, Monique Storandt, Martha Wolozin, Benjamin Boston Univ. Sch. Medicine Wyss-Coray, Anthony Stanford Univ. Xiong, Chengjie Yang, John Y-H Kaohsiung Univ. Yang, John Y-H Kaohsiung Univ. A oligomers in the aged and diseased human brain FP7 Biomarkers for Early Detection of Alzheimer s Disease Effects of ABCA1 on apoe levels in the Central Nervous System/N/A AD Progression Alcohol Effects of Statins on Human Brain Pathology Plasma proteomic markers associated with cognitive dysfunction Effects of Alzheimer s Diagnosis Disclosure Cross sectional Hypertension study/fellowship Longitudinal Hypertension study/fellowship European Union 450,000 Alzheimer s Association/ $240,000 Genome Sequencing Center/ $50,000 Washington University Washington University 1/1/ /31/ /1/2005 9/30/2007 1/1/ /31/ Tissue 120 Plasma Provide DNA-66 subjects 1331 data only 192 data only Internal support tissue John Douglas French Alzheimer s Foundation Missour State Alzheimer s Disease & Related Dementias Research Kaohsiung Medical Univ. Taiwain/ 100% Salary Kaohsiung Medical Univ. Taiwain/ 100% Salary $28,356 8/1/05-9/30/2006 8/1/05-9/30/ plasma samples 68 subjects Provide genotype for 1,353 subjects. Provide genotype for 1,922 subjects. Page 54

55 Overview Yang, John Y-H Kaohsiung Univ. Yang, John Y-H Kaohsiung Univ. Zhang, Weixiong Zlokovic, Berislav U. of Rochester ACE genotype in cases and controls/fellowship Expression of angiotensin 1- converting enzyme gene polymorphism in very mild demented and normal cognitive individuals Microarray gene expression profiling of late onset AD slrp Levels in Plasma of Alzheimer's Disease and Control Subjects N/A Kaohsiung Medical Univ. Taiwain/ 100% Salary Kaohsiung Medical Univ. Taiwain/ 100% Salary 8/1/05-9/30/ Internal support 2005 Internal support 2006 Morris, John C.. Provide genotype for 605 subjects. 393 Tissue blood 45 DNA samples 22 plasma samples from autopsy confirmed cases Page 55

56 Overview Morris, John C.. Table 3. Funding for Therapeutic Trials and Other Grants from Industry Washington University ADRC Year Since Last Competing Renewal Submission Principal Investiga Grant Title/Number Project Director A multicenter, randomized, double-blind, placebocontrolled trial of simvastatin to Galvin, James E. slow the progression of Alzheimer s disease, U01AG10483 Galvin, James E A Randomized Double Blind Placebo Controlled Trial of the Effects of Docosahexaenoic Acid (DHA) in slowing the Progression of Alzheimer's Disease A randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy Galvin, J. of MK mg in slowing the progression of Alzheimer s disease #030 Galvin, James E. CENA 713D2340 A 48 week, multicenter, randomized, double-blind, parallel-group, evaluation of the comparative efficacy, safety, tolerability of Execon 10 and 15 cm 2 patch in patients with Alzheimer s disease Galvin, James E. Effect of Gamma Secretase Inhibition on the Progression of AD NA LY450139: Tolerability and Biomarker assessment in Galvin, James E. subjects with mild to moderate Galvin, James E. Gao, Zhiyong Alzheimer s disease Phase IIA, Multicenter, Randomized, Third-party Unblinded, Adjuvant-Controlled, Multiple Ascending Dose, Safety, Tolerability and Immunogenicity Trial of ACC- 001 with QS-21 Adjuvant In Subjects With Mild To Moderate Alzheimer's Disease Study of Alzheimer's disease using in vitro methods N/A Source & Amount Project Period Role of ADC, ADCS 7/1/03-6/30/05 16 subjects ADCS 5/1/07-1/1/09 9 Subjects Merck 7/1/03-6/30/05 11 subjects Novartis Eli Lilly 3/1/ /1/ Subjects 6 Subjects Eli Lilly 7/1/04-6/30/05 8 subjects Wyeth Siemens $500,000 11/21/07-1/1/08 2 Subjects 10/1/2007-9/30/ Tissue (CDR3 hemisphere) Page 56

57 Overview Holtzman, D. Mintun, Mark Morris, John C. Morris, John C. Morris, John C. Morris, John C. Morris, John C. Morris, John C. Richard Perrin Snider, B. Joy Biomarker of Alzheimer s Disease Study (H6U MC LRAI) F-AV-138: A preliminary evaluation of the amyloid binding properties, pharmacokinetics and safety of F-AV-138 in healthy elderly volunteers and patients with Alzheimer's Disease Phase III Elan Passive Immunization with ApoE 4 carriers ELN Phase III Elan Passive Immunization with ApoE 4 carriers ELN AAB-201: Phase IIa, multicenter, randomized, double-blind, placebocontrolled, pharmacodynamic trial Acquisition of Blood and Urine Samples for Evaluation of Diagnostic Tests for Mild Cognitive Impairment and Alzheimer s Disease Assessment Measures for Alzheimer s Disease Primary Prevention Trials, U01AG10483 A Phase IIa, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose, safety, tolerability, pharmacokinetic, pharmacodynamic, and immunogenicity trial of AAD- 001 (ELN116727) in patients with mild to moderate Alzheimer's disease Assessing Different Forms of Tau Protein in Cerebrospinal Fluid as an Alzheimer Biomarker AstraZeneca Research Grant Project 2 LY : Multiple-Dose safety in Subjects with Mild to Moderate Alzheimer's Disease and Single-Dose safety in Healthy Volunteers Lilly Pharmaceutica ls Avid Radiopharmac euticals, Inc. Elan Pharmaceutic als, Inc Elan Pharmaceutic als, Inc Morris, John C.. 1/1/03-12/31/04 14 subjects 8/1/07-3/1/08 6 Subjects 05/ / / / Subjects 2 Subjects Elan 6/1/05-5/31/07 6 subjects Elan Pharmaceutic als 1/01/02-2/01/04 32 subjects, ADCS 1/1/02-1/1/05 25 subjects Elan Pharmaceutic als, Inc. AstraZeneca $127,500 1/1/2005-1/1/ / / Subjects 32 Tissue Lilly Subjects Page 57

58 Overview Morris, John C. Table 4. Fellowship/Scientist Awards and Training Grants Washington University ADRC Year Since Last Competing Renewal Submission Principal Project Funding Source/ Grant Title/Type of Award Investigator Period Amount Training Grants: Bateman, Randall Bateman, Randall, Neurology Cruchaga, Carlos Cruchaga, Carlos Kauwe, Keoni (Brent, M. PI) Kauwe, Keoni /Goate Kauwe, Keoni Liscic, Rajka Mukherjee, Odity Nupur Ghoshal, Perrin, Richard Rothman, Steve Neurology Stark, Susan In Vivo metabolism of Aß in Alzheimer s Disease Clinical Research Training Fellowship Program In Vivo Amyloid-Beta Metabolism in Humans with Alzheimer's Disease K08AG Study of 17q21 region for CBD and PSP/Fellowship Use of CSF Tau as a quantitative phenotype in AD association studies Comparison between plasma Aβ 40/42 levels and CSF Aβ 40/42 levels Research Training in Clinical Sciences/ MH14677 Use of CSF Aβ as a quantitative phenotype in AD association studies/ Fellowship Clinical discrimination of frontotemporal dementia Reducing the candidate region on 17q21 in the HDDD2 kindred Nervous System Development and Injury T32NS Nervous System Development and Injury T32NS Nervous system development and injury/training Grant Disability Prevention for Mobility Impaired Older Adults K01DD /1/04-9/30/05 9/30/05-8/31/08 4/30/ /31/ /1/08 9/30/10 4/1/97-7/ /1/ /31/2010 9/1/2005-8/31/2008 9/1/04-8/31/05 4/1/2005-9/30/ /1/82-6/30/07 9/30/07-9/29/10 American Academy of Neurology Foundation $114,000 $510,367 Navarra Government, Spain/N/A Fundacion Alfonson Martin Escudero/ 20,000 Institutional Training Grant in Genomic Science/ T32HG NIMH T32 Training Grant/N/A Ford Foundation/N/A Fullbright Scholar Fogarty International Postdoctoral Training Program/ Salary support NIH/ $239,077 NIH/ $239,077 NINDS $1,138,765 CDC $450,000 Page 58

59 Overview Morris, John C. Storandt, Martha Psychology Wilkins, Consuelo Williams, Monique Xiong, Chengjie Awards: Bateman, Randall Aging and development/training Grant AG00030 Vitamin D in Older Adults: Cognition, Mood, and Hippocampal Volume, K23AG Depression-associated inflammation in the elderly, K12AG Statistics in Alzheimer s publications K25 AG /1/02-4/30/07 9/15/06-6/30/11 7/1/06-6/30/07 9/01/05-6/30/08 $313,360/yr $823,037 $121,307 $351,608 Scientific American Top 50 Research Paper 2006 Scientific American Cirrito, John Scientific American Top 50 Research Paper 2006 Scientific American Fagan Niven, Neuroimaging Consortium New Anne Investigator Award 2006 Int l Conf. on AD Holtzman, National Academy Elected to the Institute of Medicine 2008 David M. of Sciences Holtzman, Potamkin Award for Alzheimer s, Pick s David M. and other diseases 2003 AAN Holtzman, MetLife Foundation for Medical David M. Research 2006 MetLife Foundation Holtzman, David M. Soriano Lecturer at 2006 ANA Meeting 2006 AAN Holtzman, Scientific American Top 50 Research David M. Paper 2006 Scientific American Johnson, Eugene M. AAAS Fellow 2006 AAAS Morris, John C. MetLife Foundation for Medical Research 2/2/05 MetLife Foundation Morris, John C. Potamkin Award for Alzheimer s, Pick s and other diseases 4/12/05 AAN Morris, John C. BJH Neville Grant Award for Clinical Barnes-Jewish 2006 Excellence Hospital Foundation Morris, John C. 29 th TS Srinivasan Oration 2/14/09 Chennai, India Wilkins, NMA/MCMF Distinguished Leadership & NMA/Mound City 2006 Consuelo Service Award Winner Medical Forum Page 59

60 Overview Table 5. Washington University ADRC Collaborations Morris, John C.. Washington University ADRC Year Since Last Competing Renewal Submission Institution Activity U Pittsburgh, Klunk, W. Collaboration to image amyloid in pre-clinical AD Arizona ADC & Translational Genomics Collaborated on successful R01 application for Research Institute, Stephan D, Reiman Neurogenomics of AD and Aging project E. A Longitudinal Study of Hazardous Drivers with U. Rhode Island, Ott, B Dementia, RO1 AG16335, consultation Chungbuk National University Hospital, Cell cycle biomarkers in AD Korea, Han S.-H Cooperative Studies Buckner, Randy, Howard Hughes Medical Institute (HHMI) at Harvard University Biomedical Informatics Research Network (BIRN). Dana Foundation, Klunk, W., U Pittsburgh Ferris, Stephen Open Access Series of Imaging Studies (OASIS) makes MRI data sets of the brain freely available to the scientific community to facilitate future discoveries in basic and clinical neuroscience. See description following Admin Table 2. 3 site collaboration to image amyloid in pre-clinical AD Alzheimer s Disease Centers Administrative Supplement - Improved sensitivity of robust cognitive norms Foroud, T. Indiana University National Cell Repository for Alzheimer s Disease Kramer, Patti, OHSU Genetic Associations with Alzheimer-free Survival Uniform Data Set Morris, JC PI: Neuropathology of nondemented aging collection and reanalysis of 97 control brains Roe, C. PI. Education and cognitive reserve. Cairns, N., site PI, Midwest frontotemporal dementia consortium. (with Weintraub, S, Northwestern) Kukull, W. Fagan Niven, A., PI, Proteomic Analysis of Postmortem and Ante-mortem Cerebrospinal Fluid for the University of Washington National Alzheimer s Coordinating Diagnosis of Alzheimer s Disease Center (NACC) Galvin, J. PIB in Lewy body disease (with MGH) Head, D., Feasibility of collaborative structural MRI initiative in the study of AD and FTD (with UCSD) Goate, A.: Genetics of Alzheimer's Disease and Psychosis collaborative supplement Storandt, M: Changes in Cognitive Performance in Preclinical AD: A Collaborative Analysis Mária Sasvári-Székely, Semmelweis University, Budapest, Hungary Szekely, Anna, Ph.D., Eotvos Lorand University, Budapest, Hungary Massachusetts General Hospital & Massachusetts Institute of Technology Mayeux, R. Columbia University Fogarty International Research Collaboration Award (FIRCA) on Genetic, Personality and Attention Factors in Aging and DAT Collaboration on MRI analyses and archiving Genetics Initiative for Late Onset Alzheimer's Disease Page 60

61 Overview Morris, John C.. Multiple institutions (ADCS, ADNI, NCRAD, Washington U, Indiana U, U01AG32438, Dominantly Inherited Alzheimer Harvard, Columbia, UCLA, Univ College, Network, John C. Morris, PI, was submitted London, Inst of Neurology, Queen to establish a biomarker registry of subjects from Square; Australian Consortium (Perth, families with a know mutation for AD. Brisbane, Sydney) Schellenberg, Gerald, Pittsburgh Genome Wide Association Screen Genetics of Alzheimer's Disease and Psychosis Sweet, R. U. Pittsburgh collaborative supplement-no cost extension CDR training for investigators Assessment Measures for Alzheimer s Disease Primary Prevention Trials A multicenter, randomized, double-blind, placebocontrolled trial of simvastatin to slow the progression Aisen, P. University of San Diego, Alzheimer s Disease Cooperative Study of Alzheimer s disease A Randomized Double Blind Placebo Controlled Trial of the Effects of Docosahexaenoic Acid (DHA) in slowing the Progression of Alzheimer's Disease CDR training for investigators Weiner, Michael, UCSF Alzheimer s Disease Neuroimaging Initiative (ADNI) Morris, JC, PI, ADNI Neuropathology Core Industry ASA DriveWell Driving and dementia workshop Collaborative discovery research on therapeutic Astra Zeneca options. David Holtzman, PI Automobile Association of America Foundation Celera Genomics Meuser T, PI, Medical fitness to drive and a voluntary state reporting law Collaborating on the analysis of tissue and clinical data Nova Professional, Gregory, J Dementia atlas development Pfizer Other Alzheimer's Association, St. Louis Chapter Collaborative discovery research on neuroinflammation. David Holtzman, PI Multiple events, See Education Core and Rural Satellite American Medical Association Older Drivers Project American Medical Association, Saint Collaborated with these institutions on the production Louis University School of Medicine, and execution of Dementia and Driving workshops Alzheimer s Association Barnes-Jewish Hospital Goldfarb School of Nursing Calgary Health Region-Canada, Bakal, D. Ed Cores at Oregon Health Sciences & 13 other ADCs Graduate student and faculty research fellowship, jointly sponsored by Goldfarb School of Nursing and Washington University ADRC Algorithm for the palm pilot to derive CDRs in clinical practice Co-sponsored full-day pre-conference workshop on improving dementia-related physician education at the Gerontological Society of American Annual Meeting in 11/03 (see Ed Core) Page 61

62 Overview International scholars conducting research in residence Morris, John C.. Malou Corrales, MD Visiting Scholar, The Philippines Daniela Costardi, MA, Centro Medico Richiedei, Brescia, Italy Ebru Karakoc, MD, Hacettepe University Medical Center, Ankara, Turkey Lea Grinberg, MD, University of San Paulo, Brazil Wee Shiong Lim, MD, Tan Tock Seng Hospital, Singapore Rajka Liscic, MD, Institute for Medical Research & Occupational Health, Zagreb, Croatia Nehu Parimi, MD Visiting Scholar, India Masuhiro Sakata, MD Visiting Scholar, Japan Yuan-Han Yang, MD, MS, Kaohsiung Medical University, Taiwan Katherine Mathews, MD, Siteman Collaborated on minority outreach and recruitment Cancer Center, Washington University methods Monsanto YMCA African-American outreach Nagarajan, Rakesh WU Center Translating clinical core data to ClinPortal, a webbased, clinical studies data management system Biomedical Informatics (CBMI) Produced dramatic reading of the play For Pete s St. Louis Black Repertory Company Sake for the community (See Ed Core) Joint research fellowship between the College of St. Louis College of Pharmacy Pharmacy and the Washington University ADRC supported by Novartis St. Louis Rams Renovation of Neuropathology Core laboratory Page 62

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