National Campaign on Alzheimer s Disease: A Primary Care CME Initiative

National Campaign on Alzheimer s Disease: A Primary Care CME Initiative Boston, MA November 12, 2009 12:30 PM 2:30 PM Education Partner: Mary S. Easton Center for Alzheimer s Disease Research at UCLA

Session 4: National Campaign on Alzheimer s Disease: A Primary Care CME Initiative Learning Objectives 1. Describe appropriate management of AD at its various stages, including pharmacologic therapy. 2. Identify patients who are candidates to participate in research and discuss with them the importance of participation. Faculty Robert Stern, PhD Associate Professor of Neurology Co-Director, Alzheimer's Disease Clinical and Research Program Acting Director, Clinical Core, BU Alzheimer s Disease Center Co-Director, Center for the Study of Traumatic Encephalopathy Boston University School of Medicine Teresa Gomez-Isla MD, PhD Massachusetts General Hospital MassGeneral Institute for Neurodegeneration. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Gomez-Isla has nothing to disclose. Dr Stern receives consulting fees from Elan Pharmaceuticals. Education Partner Financial Disclosure Statement The content collaborators at UCLA have reported that they have nothing to disclose. Drug List Generic donepezil rivastigmine galantamine memantine Trade Aricept Exelon Razadyne Namenda Investigational AN1792 bapineuzumab LY450139 dimebolin Acronym List Acronym AAN ACh AChE AChEI AD ADAS-cog ADL ADNI ADCS APP BuCh CJD CSF DIAN DLB DSM Definition American Academy of Neurology acetylcholine acetylcholinesterase acetylcholinesterase inhibitor Alzheimer s disease Alzheimer s Disease Assessment Scale cognitive subscale activities of daily living Alzheimer s Disease Neuroimaging Initiative Alzheimer s Disease Cooperative Study amyloid precursor protein butylcholinesterase Creutzfeldt-Jakob disease cerebrospinal fluid Dominantly Inherited Alzheimer s Disease Network dementia with Lewy bodies Diagnostic and Statistical Manual of Mental Disorders Acronym FDG IRB MCI MMSE MRI nachr NIH NINCDS-ADRDA NMDA NPI PDD PET PiB RAGE TSH Definition fluorodeoxyglucose Institutional Review Board mild cognitive impairment Mini Mental State Examination magnetic resonance imaging nicotinic ACh receptor National Institutes of Health National Institute of Neurological and Communicative Disorders and Stroke Alzheimer s Disease and Related Disorders Association N-methyl-D-aspartate neuropsychiatric inventory Parkinson s disease dementia positron emission tomography Pittsburgh Compound B receptor for advanced glycation end products thyroid stimulating hormone Session 4

Suggested Reading List Bateman RJ, Munsell LY, Morris JC, et al. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006;12:856-861. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921-923. Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology. 2007;69:1622-1634. Fagan AM, Head D, Shah AR, et al. Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol. 2009;65:176-183. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer s disease. Am J Med. 2007;120:388-397. Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology. 2007;68:1588-1595. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. Jack CR Jr, Petersen RC, Grundman M, et al. Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI. Neurobiol Aging. 2008;29(9):1285-1295. Mayeux R. Genetic epidemiology of Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:S58-S62. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001;58:1985-1992. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-2388. Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14:837-842. Boston University Alzheimer's Disease Center VA Boston Healthcare System Neurology Service (127) 150 South Huntington Avenue Boston MA 02130 Web site: http://www.bu.edu/alzresearch Information Line: 1-888-458-2823 (toll free) ADC e-mail: bmyoung@bu.edu Massachusetts General Hospital/Harvard Medical School Alzheimer s Disease Research Center Massachusetts General Hospital 114 16th Street, Room 2009 Charlestown, MA 02129 Web site: http://madrc.org Information Line: 617-726-3987 Session 4

Notes TM

Recognizing, Diagnosing, and Treating Alzheimer s Disease Robert A. Stern, Ph.D. Associate Professor of Neurology Co Director, Alzheimer s Disease Clinical and Research Program Acting Clinical Core Director, BU Alzheimer s Disease Center Co Director, Center for the Study of Traumatic Encephalopathy Boston University School of Medicine What is needed Humor Hope New Research is providing much hope! And use of cool new technology like Audience Response Systems Dementia is an inevitable part of growing old. I generally perform a brief screen with patients over the age of 65 for cognitive/memory impairment. I regularly inform/refer patients to the local services of Alzheimer s Association. Even if I suspect Alzheimer s disease as the cause of a patient s dementia, I hardly ever tell a patient that they have Alzheimer s disease. 1

Even if I feel that a patient has Alzheimer s disease, I hardly ever prescribe any medication for its treatment. What is Dementia In a nutshell: Dementia refers to a new loss of cognitive functioning that results in significant impairment in social or occupational functioning. Used to be: Senility What is Dementia Describes a syndrome; does not describe a cause. DSM Criteria for Dementia Cognitive impairment to 2 domains Memory And 1 of: aphasia, apraxia, agnosia, or disturbance to executive function Impairment to social or occupational function Decline from previous level of function No Delirium Not due to depression, etc. American Psychiatric Association. Diagnostics and Statistics Manual, Text Revision IV. 2000. Alzheimer s Disease Plaques and Tangles Accounts for approximately 75% of dementia cases. AD Differential Diagnosis (4 D s) Depression Delirium Sudden and fluctuating cognitive impairment Deficiency (e.g., thyroid, B12) Other Progressive/Degenerative Dementias Vascular Dementia, Dementia w/ Lewy Bodies (DLB), Frontotemporal Lobar Degenerations (FTLD), Chronic Traumatic Encephalopathy (CTE) Since Dr. Alzheimer first described the disease over 100 years ago, the hallmark features have been plaques and tangles seen in brain tissue. Plaques (senile plaques, amyloid plaques) are made up of a protein, called beta amyloid (Aβ42), and are found outside of the neurons. Tangles (neurofibrillary tangles) are made up of another protein, tau (phosphorylated), and are found inside neurons. 2

1. 2. 3. Amyloid Cascade: Current, widely accepted view of the pathophysiological mechanism of AD is that of an amyloid cascade: generation and deposition of Aβ42 (especially dimers and oligomers) leads to the generation and accumulation of neurofibrillary tangles, oxidative stress, inflammation, and cell death. The Amyloid Hypothesis is Not Dead Despite recent research underscoring how complex the mechanism is, as well as recent negative findings of a clinical trial for a drug aimed at decreasing amyloid, there is still overwhelming evidence that beta amyloid plays a central, early, and likely causative role in the development of AD. AD Numbers Growing AD Population Every 70 seconds, someone in the US develops AD. In US, around 5.3 million people now have AD. 13%, or 1 in 8 persons > 65 have AD ~50% or 1 in 2 > 85!! By 2030, 7.7 million Americans are expected to have AD, a greater than 50% increase over current numbers. Baby Boomers! (in 2006 BB s began turning 60 at a rate of 330 every hour) Persons (millions) Year From: Alzheimer s Association 2009 Facts & Figures Hebert LE, et al. Arch Neurology. 2003;60:1119 1122. 2008 Facts and Figures, Alzheimer s & Dementia. 4:110 133. Alzheimer s Disease is a World Crisis AD Numbers: $$$$ Persons afflicted world wide (millions) The national cost of caring for people with AD is about $148 billion every year. In 2005, Medicare spent $91 billion on beneficiaries with AD or other dementia, expected to rise to $189 billion by 2015. Average lifetime cost for an individual with AD is $170,000. Costs to businesses for employees who are dementia caregivers is $37 billion/yr. Brookmeyer R, et al. Alzheimers Dement. 2007;3:186 191. From: Alzheimer s Association 2009 Facts & Figures 3

Cost (billions of U.S. $) Projected Cost of AD in US Year 2005 2006 Progress report on Alzheimer s disease. National Institute on Aging. AD Clinical Presentation Short term memory impairment e.g., Repeatedly asking the same questions Long term memory (recall of old events/info) can be remarkably spared Impairments in visuospatial/navigational abilities e.g., Getting lost Language impairments Word finding difficulties Executive Functioning Deficits Planning, organization, multi tasking, abstraction, working memory, decision making, judgment, awareness and insight Distinguishing AD from Aging Normal Aging Retrieval deficit (responds well to clues/multiple choice) Insight retained No change in IADLs Minor delay in word finding Visuospatial function retained IADL, Instrumental activities of daily living. Farlow MR, Cummings JL. Am J Med. 2007;120:388 397. Alzheimer s disease Amnestic memory impairment (little benefit from clues or reminders); Rapid Forgetting! Insight loss IADLs compromised Anomia Visuospatial function impaired (clock draw) Apathy, withdrawal AD Risk Factors Age The Most Dramatic Risk Factor! Head Injury Increased risk, but unclear; CTE-NFL African American Many unclear issues, e.g., vascular risks, cultural effects on tests Hispanic Again, unclear, but may be effected 6-7 years earlier than non-hispanics AD Risk Factors Female Slightly greater risk in some studies. Estrogen However, prevalence of AD among women is twice as high as men simply because women live longer Low Education Cognitive Reserve AD Risk Factors, continued Additional Possible Risk Factors High Blood Pressure High Cholesterol Diabetes In other words, what s bad for the heart is bad for the brain! 4

Does it run in families Family History of Dementia increases relative risk 3-4 fold (at least up to age 80) Genetics of AD The two distinct types of AD: Early-Onset and Late-Onset Early-onset AD is rare, usually affecting people aged 30 to 60 and usually running in families. Mutations known in three genes that cause early-onset AD: Presenilin-1, Presenilin-2 ; APP Together < 2% of AD. Genetics of AD Late onset AD is more common. It usually affects people over age 65 (though lower these days because of greater surveillance) No single gene yet discovered that causes it. Susceptibility Gene: ApoE:» Having the ApoE e4 allele (the bad form of the gene) does not on its own result in AD; it increases the susceptibility, along with other factors. Similar to BRCA1/BRCA2 genes. e2 allele = protective e3 allele = neutral e4 allele = increases risk: e4/e3 3X; e4/e4 ~10X New Research: APOE status may impact efficacy of treatment and risk of side effects I feel confident about my ability to diagnose Alzheimer s dementia. Alzheimer s Disease NINCDS ADRDA Research Diagnostic Criteria The Diagnosis of Alzheimer s Disease Definite AD Characteristic neuropathology and clinical findings Probable AD No alternative disorder present Possible AD Contributing medical condition present Single cognitive function affected Unlikely AD Acute onset, focal signs, seizures, gait disturbance 5

Clinical Diagnosis of Alzheimer s Disease Without looking at actual brain tissue, the diagnosis of AD is never completely certain. The diagnosis is based on Clinical examination (including cognitive screening), History (Listen to the Caregivers/Family) Neuroimaging (CT, MRI, PET) Laboratory tests (to rule out other Dx) Neuropsychological evaluation Screening Many patients with cognitive impairment of AD are not identified in primary care In a study of 1107 subjects screened (mean age 76.3) 343 (31%) of study subjects scored 24 on the MMSE Of these, only 42 had a diagnosis of dementia Boustani M, et al. Ann Intern Med. 2003;138:927 937. Ganguli M, et al. J Am Geriatr Soc. 2004;52:1668 1675. Mini Mental State Examination Brief, structured cognitive status examination 10 minutes to administer Typical deterioration of 3 4 points per year Sensitivity and specificity vary in different patient populations Adjustments for age, education and race may be necessary Beware: Many false positives and false negatives; does not make the Diagnosis! 27 Scores Range from 0 30 26 21 20 11 Normal Mild Cognitive Impairment Moderate Cog. Impairment 10-0 Severe AD Folstein MF, et al. J Psychiatr Res.1975;12:189 198. Boustani M, et al. Ann Intern Med. 2003;138:927 937. Galvin JE. Applied Neurology. 2005;(supplement):1 16. Zadikoff C,et al. Mov Disord. 2008;23:297 299. Borson S, et al. Int J Geriatr Psychiatry. 2000;15:1021 1027. Geldmacher DS. Prim Care Companion J Clin Psychiatry. 2007;9:113 121. The AD8 Informant Interview Informant based questionnaire that can be administered at home or in waiting room Detects change compared with previous level of function No need for baseline Patients serve as their own control Minimally affected by education, race, gender Brief (<3 minutes), yes/no format 2 or more yes answers highly correlated with presence of dementia Sensitivity 85%, Specificity 86% Galvin JE, et al. Neurology. 2005;65:559 564. Rapid Screen for Cognitive Impairment: Mini Cog 5 minutes to administer 1) 3 word registration 2) Simple clock drawing test 3) 3 word recall Diagnostic value not influenced by education level or language Sensitivity 99% Specificity 93% Mini Cog Recall 0 Recall 1 2 Recall 3 Demented Abnormal Clock Demented Non Demented Normal Clock Non Demented Formal Neuropsychological Evaluation Referrals for neuropsychological evaluation are useful in diagnostic workup Tests that focus on (anterograde) memory may be most useful May be particularly relevant in determining likelihood to progress from MCI to AD Useful in distinguishing among dementias Useful in distinguishing normal aging (with and without depression) from mild dementia Borson S, et al. Int J Geriatr Psychiatry. 2000;15:1021 1027. Monsch AU, et al. Arch Neurol. 1994;52:899 904. 6

I usually order neuroimaging as part of my dementia work up. Neuroimaging and Biomarkers Support a Diagnosis of AD MRI/CT Rule out other causes Hippocampal/Temporal lobe atrophy CSF Analysis Decreased Aβ/Increased Tau PET/SPECT/fMRI Bilateral temporal or parietal lobe hypo function No Dementia MCI Function Dementia Potential Treatment Outcomes in Alzheimer s Disease Prevention Cure Slow Progression There is nothing that can be done to prevent Alzheimer s. Delay Decline Time Prevention and Delay Prevention: Decrease Heart Risk If we can delay the onset of AD by just FIVE years, we can cut in half the number of people with the disease! So, Prevention and/or Delay is critical. 7

Polyphenols Antioxidants Flavanoids Omega 3 Fatty Acids Resveratrol Prevention: Diet Alcohol and AD Recent research suggests: Moderate alcohol consumption (1 2 drinks/day) may decrease risk of AD ONLY if no other contraindications! More than moderate drinking may INCREASE risk of AD Once there is any cognitive impairment, continued drinking increases risk. Sink et al., 2009, ICAD Prevention: Lose Weight Being fat in your 40s might raise your risk of developing dementia later in life. In a study published in the British Medical Journal (Whitmer et al., 2005), researchers found that the fatter people were, the greater their risk for AD. This was based on a study of more than 10,000 Californians who were followed for almost 30 years. Obesity, defined as a Body Mass Index of > 30, was a particularly serious risk factor for women. Obese women were twice as likely to develop dementia than women of healthy weight, while obese men were only slightly more likely to develop the disease. Prevention: Exercise In a report in Annals of Internal Medicine (Larson et al., 2006), regular exercise was found to delay the onset and reduce the risk of developing AD, and the more frail a person was, the more she or he benefited from exercise. 8

Prevention: Exercise Prevention: Intellectual Stimulation A mouse study suggests that exercise may prevent beta amyloid deposition, thereby lowering the risk of developing AD. Adlard et al., J Neuroscience, 2005 Intellectual Stimulation: What seems to work best Try new things and new ways. Take up a new language. Take a new route. Try new recipes. Read a different type of book. Start a new hobby or rekindle an old one. Do the computerized brain health methods work Yes and No it doesn t hurt. Prevention: OTCs Alzheimer s Cocktails Ibuprofen Vitamin E Glucosamine Curcumin Fish Oil DHA Ginkgo Biloba Nope! No Evidence in Support Prevention: Medication NSAIDS stay tuned ADAPT study at BU Statins Unclear Estrogen Nope Angiotensin Receptor Blockers new findings by Wolozin Donepezil and other cholinesterase inhibitors have a direct impact on the underlying causes of Alzheimer s disease. 9

Once Alzheimer s Disease Begins If the disease begins, there is no cure. But, there currently are prescription medications available that are geared specifically for AD. The three somes of current treatments some symptomatic relief some patients some duration. Symptomatic Therapies Generic Name Target (Action) Dosing FDA Approval Donepezil (tablets and orally disintegrating tablets) - Rivastigmine Rivastigmine Patch Galantamine ER Memantine (tablets and oral solution) - AChE (inhibition) 5, 10 mg q.d. Mild AD Moderate AD Severe AD AChE (inhibition) BuChE (inhibition) AChE (inhibition) BuChE (inhibition) AChE (inhibition) nachr (modulation) NMDA Receptor (antagonism) 1.5, 3, 4.5, 6 mg b.i.d. (with food) 4.6 (5 cm 2 ), 9.5 (10 cm 2 ) mg/d 8, 16, 24 mg q.d. (with food) Mild AD Moderate AD Mild/Mod PDD Mild AD Moderate AD Mild/Mod PDD Mild AD Moderate AD 5, 10 mg b.i.d. Moderate AD Severe AD Symptomatic Therapies Can Provide Long Term Benefit Combination Therapy is Safe and Effective All patients received donepezil therapy Raskind MA, et al. Arch Neurol. 2004;61:252 256. Tariot PN, et al. JAMA. 2004;291:317-324. Synergistic Effect of Combination Therapy Progression over time on the Blessed Dementia Scale is slowed with combination therapy relative to ChEI therapy alone and no AD meds Approved Therapies for AD Delay Nursing Home Placement Atri A, et al. Alz Dis Assoc Dis. 2008;22:209-221. Lopez OL, et al. J Neurol Neurosurg Psychiatry. 2009;epub. 10

Adverse Events Donepezil: Nausea, vomiting, diarrhea, anorexia, insomnia, muscle cramps, fatigue, syncope Rivastigmine: Nausea, vomiting, anorexia, weight loss, dyspepsia, asthenia, dizziness, fatigue, diarrhea, skin reaction (to patch); GI Sx less with patch Galantamine: Nausea, vomiting, anorexia, weight loss, syncope, fatigue, dizziness, dyspepsia, diarrhea Memantine: Dizziness, headache, confusion, constipation, hypertension, coughing, vomiting, back pain, somnolence No clinical benefit Switch AChEI therapy No clinical benefit to ANY AChEI Substitution of memantine in moderate AD Treatment Algorithm Diagnosis of AD First-line: AChEI therapy (titrate to maximal tolerated dose) No clinical benefit to AChEI monotherapy Addition of memantine in moderate AD Clinical benefit Maintain AChEI therapy & monitor Farlow MR, Cummings JL. Am J Med. 2007;120:388 397. Treatment failure/loss of clinical benefit Adapted from: Farlow MR, Cummings JL. Am J Med. 2007;120:388 397. Withdrawal of AChEI and/or memantine therapy Cessation of Therapy Consult the family Keep in mind: hope and placebo effects Monitor during withdrawal Behavior Function Cognition Once meaningful social interactions are no longer possible Behavioral Symptoms in AD Will occur in 90% of AD patients % Participants MCI, mild cognitive impairment. NPI, neuropsychiatric inventory, Total NPI=any symptom. Haupt M, et al. Dement Geriatr Cogn Disord. 2000;11:147-152. Lyketsos C, et al. JAMA.2002;288:1475-1483. Behavioral Symptoms in AD Difficult to handle in primary care setting Require additional Attention Caregiver counseling Staff Referral to support systems Nonpharmacologic Strategies for Behavioral Symptoms Depression: maintain cheerful environment, encourage exercise and social interaction, redirect negative thoughts Agitation/aggression: identify potential triggers, establish calm environment, avoid arguing, be flexible, usefulness of touch/intimacy Repetitive behavior: ignore some repetitive questions, redirect attention Delusions/hallucinations/paranoia: avoid confrontation and reasoning, give noncommittal answers, understand the reality of the patient Guerriero-Austrom M, et al. Gerontologist. 2004;4:548-553. 11

Medical Recommendations for Behavioral Symptom Management Anti AD meds may help behavioral symptoms SSRIs have supportive data Tricylics and benzodiazepines should be avoided Conventional and atypical antipsychotics Mixed efficacy results, mostly for agitation Safety considerations (stroke and death)! Cummings JL, et al. Alzheimer s Dement. 2008;4:49-60. McKeith I, Cummings J. Lancet Neurol.2005;4:735-742. Patient/Family Education and Support Integrate medical care and support Do not try and manage all of the patient s and family s needs alone. Alzheimer s Association (800) 272 3900 www.alz.org Geriatric Care Managers Be aware of caregiver stress and limitations Discuss diagnosis and treatment Involve early stage patients Discuss progression Discuss decisional capacity and end of life decisions Mild Cognitive Impairment (MCI) is a meaningful clinical diagnosis. Mild Cognitive Impairment (MCI) Now clear that AD disease process begins years or decades prior to symptoms and diagnosis MCI is a clinical construct that distinguishes a patient from their age cohort Memory complaint Objective impairment for age No impairment of activities of daily living High likelihood of progression to AD May not progress and may improve Can progress to other dementia (~30%) Petersen RC, et al. Neurology. 2001;56:1133 1142. MCI Management MCI should be recognized and monitored for cognitive and functional decline due to increased risk for subsequent dementia AAN To date, no clinical trial has demonstrated efficacy on a primary endpoint for treatment of MCI To date, no treatment study has demonstrated delayed progression from MCI to dementia Petersen RC, et al. Neurology. 2001;56:1133 1142. Salloway S, et al. Neurology. 2004;63:651 657. Doody RS, et al. Neurology. 2009; epub ahead of print. Petersen RC, et al. N Eng J Med. 2005;352:2379 2388. Feldman HH, et al. Lancet Neurol. 2007;6:501 512. Winblad B, et al. Neurology. 2008;70:2024 2035. I will regularly perform the MMSE or another cognitive screen in patients over the age of 75. 12

I will regularly perform the MMSE or another cognitive screen in patients over the age of 65. I will inform patients of the services of offered by the Alzheimer s Association. I routinely refer my patients with Alzheimer s disease to centers conducting clinical research. Research In Alzheimer s Disease: Cause for Hope and Referral Teresa Gomez Isla MD, PhD Massachusetts General Hospital MassGeneral Institute for Neurodegeneration. I have previously referred an Alzheimer s patient for participation in research. What factors keep you from referring patients to Alzheimer s research 1. Nothing, I refer all the time 2. I don t want to lose my patient 3. There s nothing out there that can help the patient more than I can 4. It s inconvenient to me 5. It s inconvenient to my patient 6. I lack information for proper referrals 13

Growth of AD Population Projected Cost of AD Persons (millions) Cost (billions of U.S. $) Year Year Hebert LE, et al. Arch Neurology. 2003;60:1119 1122. 2008 Facts and Figures, Alzheimer s & Dementia. 4:110 133. 2005 2006 Progress report on Alzheimer s disease. National Institute on Aging. Research May Be the Answer Goals in Alzheimer s Disease Research 1. Earlier diagnosis Biomarkers of disease a. MRI b. CSF c. PET/fMRI d. Amyloid (and other disease marker) imaging 2. Disease modifying therapies 3. Better symptomatic therapies Difficulty in recruiting patients Low Subject Recruitment Hinders Research Progress Reason for lost days [toward deadline for clinical trial completion] 85 95% 5 15% Other Cruz Rowe J, et a. The McKinsey Quarterly. 2002;2:134 141. Older Patients in Clinical Trials Age distribution should reflect that of the target disease Efforts to include the very elderly should be addressed Sufficient numbers of elderly and very elderly to assess Safety Risks Benefits Ethics of Elderly Inclusion Those who bear the inconvenience and risk associated with research participation must be representative of those who will benefit Elderly candidates for research are rarely encouraged to participate Upper age limits should be excluded or thoroughly justified in research protocols International Conference on Harmonisation of Technical Requirement for Registration for Pharmaceutical for Humans. Final Concept Paper; E7 (R1) Studies in Support of Special Populations: Geriatrics. National Commission for the protection of human subjects of biomedical and behavioral research. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Washington, DC: US Government Printing Office, 1979. Bayer A, Fish M. Drugs Aging. 2003;20:1087 1097. Kemeny M, et al. J Clin Oncol. 2003;21:2268 2275. 14

Patient Safeguards Institutional Review Board (IRB) Informed consent Document Process Benefits of Participation Active role in own health care Access to new treatments before they are widely available Specialist medical care and cutting edge technologies at academic institutions Help others by contributing to medical research Often free of charge High satisfaction rating Human Clinical Trials: The Limiting Factor Trial Referral is an Underused Opportunity Ever referred for an AD trial Have patients/caregivers approached about an AD trial Many Potential Treatments Clinical Trials Great Public Need 22% 39% Bottleneck 78% 61% Dr. Jeffrey Cummings Alzheimer s Association Physician Study. Final Report. February 2007. Trial Awareness is a Missing Link Are you aware of clinical trials in your area 21% 79% Why Refer Clinical Research Participants Without referrals, new medications, diagnostic tools, and cure will be delayed Research participation is not a substitute for routine clinical care subjects continue to see own physician Opportunity for mutual referral relationships Tertiary care research centers cannot see patients in primary clinical capacity and need referral options Enhance practice credibility Alzheimer s Association Physician Study. Final Report. February 2007. 15

Early Diagnosis is Important Initiate treatment Delay decline Allow advance directives Allow last events Research is Leading to Earlier Diagnosis Proposed Research Diagnostic Criteria 1. Episodic memory impairment 2. Biomarker for AD MRI FDG PET PIB PET CSF Aβ/ Tau Dubois B, et al. Lancet Neurol. 2007;6:734-746. Research Suggests Amyloid Protein is Central to AD Amyloid Imaging Shows Amyloid in the Brain in AD LaFerla F, et al. Nat Rev Neurosci. 2007;8:499-509. Klunk W, et al. Ann Neurol. 2004;55:306-319. Amyloid Imaging Shows Amyloid in Some MCI and Some Normal Elderly Other Biomarkers Identify Early AD MRI: hippocampal volume, cortical thickness mapping CSF: decreased Aβ, increased Tau PET: bilateral temporal or parietal hypometabolism Price JL, et al. J Cereb Blood Flow Metab. 2005;25:1528-1547. 16

Hippocampal Atrophy is a Marker for AD CSF Levels Predict Progression from MCI to AD Pathological CSF: Aβ 42 : <530 ng/l T tau: >350 ng/l Sensitivity: 95% Specificity: 83% MCI population: Peterson criteria Memory complaint Excluded causes of impairment but not white matter changes or depression Mosconi L. Eur J Med Mol Imaging. 2005;32:486-510. Hansson O, et al. Lancet Neurol. 2006;5:228 234. Peters RC, et al. Arch Neurol. 1999;56:303 308. FDG PET Hypometabolism in amci and AD ADNI study of 74 probable AD, 142 amci subjects, and 82 NC AD and amci show hypometabolism in: Posterior cingulate Precuneus Parietotemporal cortex Frontal cortex Alzheimer s Disease NeuroImaging Initiative (ADNI) Five year study (inception: Oct 1 2004) Examine rate of change Cognition Function Brain structure and function Biomarkers 200 elderly controls, 400 MCI, 200 AD Public access of clinical and imaging data www.adni info.org www.loni.ucla.edu/adni/ Langbaum JBS, et al. NeuroImage. 2009;45:1107 1116. Genome Wide Association Study NIA funded project among AD centers Currently 95% complete Allows for study of whole genome or individual genes of interest More than 620,000 markers available Linked to neuroimaging and other biomarker data Available to all investigators www.loni.ucla.edu/adni Dominantly Inherited Alzheimer s Network (DIAN) International partnership to study familial form of AD Rare form (~2% of all cases) Caused by genetic mutations to APP, PS1, PS2 genes Expected to provide information important to sporadic AD 17

New Treatments Are Evolving That May Prevent or Treat AD Anti amyloid drugs Anti amyloid antibodies Neuroprotective All studies need patients in trials. Current Therapies in Phase III Development Bapineuzumab: Passive immunization with humanized monoclonal antibodies against Aβ 42 LY450139: Gamma secretase inhibitor Dimebolin: Mitochondrial pore stabilizing agent Gilman S. ICAD Presentation. 2008. Fleisher AS, et al. Arch Neurol. 2008;65:1031-1038. Doody RS, et al. Lancet 2008;372:207-215. Cummings JL. ICAD Presentation. 2008. Vaccination in Human Patients (AN1792) Immunized Nicoll JA, et al. Nature Medicine. 2003;9:448-452. Parietal Cortex Un-Immunized Control Dimebolin Treatment Preserved Cognition and Memory for 18 Months Mean change from baseline (SE) -6-3 0 3 6 9 * 12 Open-label Week 65 Week Baseline Week 12 Week 26 Week 39 Week 52 78 0Placebo-controlled -1.7-2.17 Phase -2.14-1.23Extension 0.96 Phase 1.66 Dimebon Placebo 0 0.32 1.78 3.79 5.63 Cummings, JL. ICAD Presentation. 2008. ** ** Baseline 12 Months 18 Months ** Clinical Improvement Clinical Deterioration * p < 0.01; ** p < 0.0001 versus placebo Alzheimer s Disease Cooperative Study (ADCS) Formed in 1991 Partnership between NIA and UCSD Facilitate discovery, development, testing of new drugs for treatment of AD Part of the Alzheimer s Disease Prevention Initiative www.adcs.org Receptor for Advanced Glycation Endproducts (RAGE) and Aβ RAGE is a cell-surface receptor expressed by many CNS cells including neurons RAGE binds Aβ Promotes inflammation and glial activation Feeds forward (further increase in RAGE expression) Aβ transport at the BBB AGEs may be neurotoxic and increase oxidative stress Blocking RAGE may decrease pathologic events in AD 18

All of These Studies Need Your Help Primary Care Practitioners Academic Medical Centers NEW DISCOVERIES NIH Interaction Between Primary Care and Academia is Critical to Helping Patients Patients and providers want better treatments Patient participants are critical to research advances With research, better diagnosis and treatment will be come available NEW THERAPIES Summary Tremendous ongoing research efforts Better diagnosis Better treatments Research can not move forward with out participants Primary care providers are well positioned to facilitate research advances through participant referral I intend to inform patients with Alzheimer s disease of the opportunities to participate in research 19