NIA Science Advances Update. NIA Science Advances

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1 NIA Science Advances 2016 Update NIA Science Advances Richard J. Hodes, M.D. Director National Institute on Aging Visit from Friends of the NIA October 7, 2016

2 NATIONAL INSTITUES OF HEALTH National Institute on Aging Organizational Structure Office of the Director Richard J. Hodes, M.D. Marie A. Bernard, M.D. Intramural Research Program Luigi Ferrucci, M.D., Ph.D. Michele K. Evans, M.D. Division of Extramural Activities Robin Barr, D.Phil. Chyren Hunter, Ph.D. Division of Aging Biology Felipe Sierra, Ph.D. Ronald Kohanski, Ph.D. Division of Behavioral and Social Research John Haaga, Ph.D. Georgeanne Patmios, M.A. Division of Neuroscience Eliezer Masliah, M.D. Creighton Phelps, Ph.D. Division of Geriatrics and Clinical Gerontology Evan Hadley, M.D. Winifred K. Rossi, M.A.

3 Intramural Research Program 10 Intramural Laboratories Core facilities Home of the BLSA and HANDLS

4 Is Metformin the Magic Elixir for Aging? mirnas Dicer Metformin AGE Dicer Mock Metformin SA-β-Gal Senescence Markers p16, p21 SASP Metformin decreases cellular senescence Hooten, T et al. (2016) Aging Cell 15(3):

Role of Myelin in Human Brain Function MR image

Myelin sheaths Rapid conduction of nerve

-Brain development -The pathophysiology of CNS

Phenylketonuria * Schizophrenia * Epilepsy *

5 Role of Myelin in Human Brain Function MR image of human brain Nerve axon microstructure Myelin Myelin sheaths Rapid conduction of nerve impulses Myelination is an important feature of -Brain development -The pathophysiology of CNS disorders: * Multiple sclerosis * Phenylketonuria * Schizophrenia * Epilepsy * Alzheimer's disease Bouhrara, M et al. (2016). Neuroimage 127:

Mapping Myelin in Human Brain MRI scanner MR Images Image acquisition A

new method for high resolution myelin mapping - Whole brain coverage can be

step toward understanding the relationship between myelination in mild

6 Mapping Myelin in Human Brain MRI scanner MR Images Image acquisition A series of images covering the whole brain volume area - We have developed a new method for high resolution myelin mapping - Whole brain coverage can be achieved in less than 15 min Conventional Method New Method* - An important step toward understanding the relationship between myelination in mild cognitive impairment and Alzheimer s disease. Bouhrara, M et al. (2016). Neuroimage 127:

7 Higher midlife adiposity is associated with earlier age at onset (AAO) of AD Midlife BMI and AAO of Alzheimer s Disease (AD) (N=142) Each incremental unit in midlife BMI is associated with an earlier age-of-onset of AD by an average of 6.7 months Relationship between 10 th percentile survival time for Alzheimer s dementia (AD) and midlife BMI with 90% confidence intervals Chuang, Y (2015) Mol Psychiatry 21(7):910-5.

8 Three new risk loci for myasthenia gravis Chuang Y. F Mol Psychiatry 21(7):910-5 Renton, A et al. (2015) JAMA Neurology 72(4):

9 Translating genetic findings to help patients with myasthenia gravis Clinical trial of Abatacept in myasthenia gravis patients to start at Johns Hopkins in late 2016/early 2017 Renton, A et al. (2015) JAMA Neurology 72(4):

Division of Aging Biology Nathan Shock Centers of Excellence Genetics and Cell Biology Genetics Cell Biology Metabolic Regulation Aging Physiology Cardiovascular Biology Immunology Endocrinology

10 Division of Aging Biology Nathan Shock Centers of Excellence Genetics and Cell Biology Genetics Cell Biology Metabolic Regulation Aging Physiology Cardiovascular Biology Immunology Endocrinology Musculoskeletal Biology Stem Cell Biology Tissue Physiology Biological Resources Animal Models Biological Resources Naked Mole Rats Director: Felipe Sierra, Ph.D. Deputy Director: Ron Kohanski, Ph.D.

11 Ismail, K et al (2016) J Am Geriatr Soc (8): Appearance of all diseases in relationship to age NECS-New England Centenarian Study (Perls) LGP-longevity Genes Project (Einstein) F-females M-males C-control P-proband (centenarians)

12 JAK inhibition alleviates inflammation Xu, M. et al. (2015) PNAS 17;112(46):E

13 Senescent Cells have Beneficial Functions De Maria, M et al. (2014) Dev Cell 31(6):

14 Menopause accelerates the epigenetic clock Levine, ME et al. (2016) PNAS 113(33):

15 DNA Methylation and health disparities Ethnicity Gender Horvath, S et al. (2016) Genome Biol 17(1):171.

NIH GeroScience Interest Group (GSIG) Trans-NIH organization of 21 Institutes initiated by NIA to: Raise awareness of the relevant role played by aging biology in the development of diseases and

16 NIH GeroScience Interest Group (GSIG) Trans-NIH organization of 21 Institutes initiated by NIA to: Raise awareness of the relevant role played by aging biology in the development of diseases and disabilities. Promote discussion and co-funding of initiatives across the NIH, based on the above. Gero I 2013 Summit Gero II - Disease Drivers of Aging: 2016 Advances in Geroscience Summit- focused on how diseases and associated therapies can accelerate the onset of agerelated changes

17 Division of Neuroscience Basic Neurobiology Alzheimer s Disease Sensory Processes Learning and Memory Sleep Cognitive Health Director: Eliezer Masliah, M.D. Deputy Director: Creighton Phelps, Ph.D. phelpsc@nia.nih.gov

18 The Busier the Better? An observed association: Increases in busyness are associated with improved cognition Festini, SB et al. (2016) Front Aging Neurosci 17;8:98

19 Genetic Regions of Interest in Alzheimer s Disease By year of discovery NOTE: Color indicates mechanism of action in the body. See key below. APP APOE PS1 PS2 CR1 CLU PICALM BIN1 CD33 SORL1 CD2AP MS4A4/MS4A6E EPHA1 TREM2 ABCA7 HLA-RB5 TRIP4 MAPT MEF2cC PTK2B FERM T2 CASS4 NME8 CELF1 IMPP5D SLC24A4/RIN5 KEY Early-onset genes Innate immune/brain inflammatory response genes Endocytosis and cellular protein trafficking, including APP trafficking and Aβ processing Lipid transport/metabolism Synaptic transmission Cytoskeletal function, including tau No assigned mechanism of action

20 Biomarkers Inform Our Understanding of Alzheimer s Progression Jack, C et al. (2013) Lancet Neurol 12(2):

21 Clinical, Cognitive, Structural, Metabolic, and Biochemical Changes years Before AD Symptom Onset Bateman, R et al. (2012) N Engl J Med 367 (9):

22 Aβ Deposition in Autosomal Dominant Alzheimer's Disease Years before Expected Clinical Symptoms. Courtesy of Tammie Benzinger; Bateman, R et al. (2012) N Engl J Med 367(9):

Decreased smell identifies risk for Alzheimer s Disease Almost 25% of patients with low University of Pennsylvania Smell Identification Test

23 Decreased smell identifies risk for Alzheimer s Disease Almost 25% of patients with low University of Pennsylvania Smell Identification Test (UPSIT) scores transitioned to AD compared to less than 5% of patients who scored the highest Devanand, D et al. (2015) Neurology 84(2):

24 Relationship between sleep and amyloid load >7 h > 6 h to 7 h 6 h Mean PET PiB images show increased amyloid burden in those subjects who report sleeping less than 6 hours nightly Spira, A et al. (2013) JAMA Neurology 70(12):

Basic & Translational Projects in the 25 AD Pipeline A consortium to look at how vascular risk factors influence AD focused on molecular mechanisms New translational centers to develop and share the

25 Basic & Translational Projects in the 25 AD Pipeline A consortium to look at how vascular risk factors influence AD focused on molecular mechanisms New translational centers to develop and share the next generation of animal models of AD A biomarkers consortium to study AD in individuals with Down syndrome Discovery and development of novel therapeutics for AD against a wide range of targets Facilitated by AMP Target Discovery and Preclinical Validation Shortens the time between discovery of targets to development of new drugs Integrates analysis of large-scale molecular data from human brain samples with network modeling approaches and experimental validation

26 Young Blood Plasma Affects Memory in Amyloid Precursor Protein (APP) Mice Circulating factors within young blood were sufficient to restore abnormal gene and protein expression in APP mice Middeldorp, J et al. (2016) JAMA Neurology Epub ahead of print.

Division of Behavioral and Social Research Reversibility of earlyestablished risk factors Regional and int l differences in health and longevity Social neuroscience of aging

27 Division of Behavioral and Social Research Reversibility of earlyestablished risk factors Regional and int l differences in health and longevity Social neuroscience of aging Longitudinal Studies Centers programs Interventions c/o Gerontology Society of Iowa Director: John Haaga HaagaJ@mail.nih.gov Acting Deputy Director: Georgeanne Patmios patmiosg@nia.nih.gov

Episodic Memory in Older Adults Enhanced by Productive Engagement Episodic Memory Standardized Gain Score Condition Episodic memory was enhanced

28 Episodic Memory in Older Adults Enhanced by Productive Engagement Episodic Memory Standardized Gain Score Condition Episodic memory was enhanced in these productive-engagement conditions relative to receptive-engagement conditions. Park, D et al. (2013) Psychological Science 25 (1):

29 Negative Stereotypes about Aging Predict AD Biomarkers Biomarkers for AD include: decreased hippocampal volume, amyloid plaques, and neurofibrillary tangles The hippocampus is a critical brain region for maintenance of intact memory People who held negative stereotypes about aging 20 years prior to brain assessments showed steeper declines of hippocampal volume than people holding positive aging stereotypes Levy, B et al. (2016) Psychol Aging 31(1):

Negative Stereotypes about Aging Predict AD Biomarkers Biomarkers for AD include: decreased hippocampal volume, amyloid plaques, and neurofibrillary tangles The hippocampus is a critical brain region

30 Negative Stereotypes about Aging Predict AD Biomarkers Biomarkers for AD include: decreased hippocampal volume, amyloid plaques, and neurofibrillary tangles The hippocampus is a critical brain region for maintenance of intact memory People with negative age stereotypes - measured 20 years prior to brain assessments - had greater accumulations of amyloid plaque and neurofibrillary tangles Levy, B et al. (2016) Psychol Aging 31(1):

31 Improving Inappropriate Antibiotic Prescribing Accountable justification Peer comparison Both behavioral interventions resulted in lower rates of inappropriate antibiotic prescribing Meeker, D et al. (2016) JAMA 315(6):

Division of Geriatrics and Clinical Gerontology Older Americans Independence Centers Menopause Cardiovascular Disorders Cancer and Aging Exercise and

32 Division of Geriatrics and Clinical Gerontology Older Americans Independence Centers Menopause Cardiovascular Disorders Cancer and Aging Exercise and Physical Activity Osteoporosis/ Musculoskeletal Disorders Director: Dr. Evan Hadley, M.D. Deputy Director: Winnie Rossi, M.A.

33 Diet and/or Exercise to Treat Heart Failure With Preserved Ejection Fraction Kitzman, D et al. (2016) JAMA 315(1):36-46.

34 Early versus Late Postmenopausal Treatment The study tested the effects of menopausal hormone therapy on atherosclerosis depending on the timing of the initiation of therapy (< 6 years vs. 10 years post menopause) A trial testing effects of hormone therapy on prevention of heart attacks, cardiac death, and stroke is needed to establish clinical significance of these findings with Estradiol (ELITE) Trial Hodis, H et al. (2016) N Engl J Med 374:

35 Effects of Testosterone Treatment in Older Men Snyder, P et al. (2016) NEJM 374(7):

SPRINT Follow-up in Adults 75 years or Older Cumulative hazard was reduced in participants, even those less fit and frail Incident cardiovascular disease was reduced by 33% and mortality (from any

36 SPRINT Follow-up in Adults 75 years or Older Cumulative hazard was reduced in participants, even those less fit and frail Incident cardiovascular disease was reduced by 33% and mortality (from any cause) was reduced by 32% Williamson, J et al. (2016) JAMA 315(24): The rate of serious adverse events was not statically different across treatment groups, including among the most frail participants

37 STrategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) A trial of a multifactorial, evidence-based, patientcentered fall injury prevention strategy 6000 community-living adults aged 75 years who are at increased risk for serious fall injuries will be enrolled and followed for up to 36 months The project is a collaboration of researchers from 14 Claude D. Pepper Older Americans Independence Centers, practitioners from 10 healthcare delivery systems and patient representatives- funded by NIA and PCORI It is expected to be completed in 2019

38 What s on the horizon?

39 New Alzheimer s Concepts Division of Aging Biology Comparative Biology of Neurodegeneration Dynamic interactions between Peripheral Systems and the Brain in Aging and in Alzheimer s Disease Systems biology approaches to Alzheimer s Disease using Non- Mammalian Models The role of aging metabolic changes in Alzheimer s disease (AD) The Role of Peripheral Proteostasis on Brain Aging and on Alzheimer s Disease Division of Behavioral and Social Research Improving Quality of Care and Quality of Life for Persons with Alzheimer s Disease and Related Dementia at the End of Life Leveraging Existing Cohort Studies to Clarify Risk and Protective Factors for Alzheimer s disease and related dementias

40 New Alzheimer s Concepts Division of Neuroscience Brain lymphatic system in aging and Alzheimer s disease Commonalities, and Interactions Between Neurodegenerative Diseases Human Cell Reprogramming for Functional Genetics of Alzheimer s Disease Mechanisms of Selective Neuronal Vulnerability in Alzheimer s Disease NIA Small Business Opportunities to Advance Alzheimer s Disease Research Revision Applications to Enhance the Target and Biomarker Discovery Efforts of the AMP-AD and M2OVE-AD Consortia Role of Exosomes in Alzheimer s Disease Validation of NIH Toolbox Instruments for Tracking and Diagnosis of MCI and early AD, and for Extension of Assessment in the Oldest Old Understanding the Impact of Sex Differences on the Phenotypes of AD Risk and Responsiveness to Therapy Complex Biology of Resilience from Alzheimer s

41 New Alzheimer s Concepts Division of Geriatrics and Clinical Gerontology Clarifying the relationship between delirium and Alzheimer s disease and related dementias Development of Socially Assistive Robots to Engage Persons with ADRD and their Caregivers Multimorbidity in Alzheimer s Disease Impacts Choice of Ancillary Treatments Pragmatic Trials for Dementia Care in Long Term Services and Support (LTSS) Settings Tools for Clinical Care and Management of Alzheimer s disease and its comorbidities Understanding the Effects of APOE2 on the Interaction between Aging and Alzheimer s Disease.

42 New Alzheimer s Concepts Division of Extramural Activities Alzheimer s Disease Research Revision Awards to Institutional Training Grants Institutional Training Programs to Advance Translational Research for Alzheimer s Disease and AD Related Dementias Research Career Enhancement Award to Advance Therapy Development for AD and Related Dementias

Genetic Heterogeneity of Clinically Defined AD. Andrew J. Saykin, PsyD Indiana ADC ADC Clinical Core Leaders Meeting April 22, 2017

Genetic Heterogeneity of Clinically Defined AD Andrew J. Saykin, PsyD Indiana ADC ADC Clinical Core Leaders Meeting April 22, 2017 Disclosures & Acknowledgements Disclosures Eli Lilly (Collaborative Grant),