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Neuropsychology of Aging and Dementia: Advances in Clinical Diagnosis, Treatment & Prevention Kathleen A Welsh Bohmer PhD, ABPP CN Professor of Psychiatry & Neurology Duke University Financial Disclosure Research Support: Takeda and Zinfandel Pharmaceutical Companies for my role as Neuropsychology Lead to the Global TOMMORROW clinical trial program Consultant with technology and pharmaceutical companies: Muses Laboratories, NeuroCog Trials, GSK, Lilly, J&J, Biogen, Merck, T3D therapeutics, and Diffusion Pharmaceuticals Board Member to AlzNC, a local nonprofit group in NC 1

Here is Jane Jane has been noticed some embarrassing problems with her memory for about a year now, ever since she retired and sold her business She has difficulty tracking conversations and she is now more likely to repeat herself, unsure with whom she may have shared recent updates about her children and grandchildren Laboratory tests and even brain imaging studies all are normal But Jane knows that Alzheimer s disease runs in her family She has always been prepared for the possibility that this disease might also affect her one day 2

Her family reassures her, pointing out how capable she is in all her activities Her primary care doctor tells her that her concerns are normal and nothing more than age Laboratory tests and even brain imaging studies all are normal Is that one day now here? Do I have Alzheimer s disease or is this just what I should expect with normal aging? Isn t there some type of test I can take to tell me for sure? And if it is the disease what can I do about it? 3

Alzheimer s disease (AD) is one of the most dreaded conditions, among the most feared diagnoses for adults over the age of 65 Recent surveys indicate that 94% of physicians disclose diagnosis of terminal cancer Same group of physicians are reluctant to disclose the diagnosis of Alzheimer s disease to their patients Blendon RJ et al Key Findings from a Five Country Survey of Public Attitudes about Alzheimer s Disease Data from the Harvard School of Public Policy and Alzheimer s Europe study (2011) Population Growth in Aging Sector (Aged 60+ years) ~Ten years ago, world wide estimates of AD projected that there were 24 26 million with dementia and that growth to 423 million by 2020 & 106 million by 2050 Many countries expected to have most impact: growth of population in 60+ anticipated not well represented in early survey work Regions well covered Some * studies Single studies Worldwide Prevalence studies: from Delphi Consensus study of Ferri et al, Lancet 2005, 366 4

Population Growth in Aging Sector (Aged 60+ years) ~Ten years ago, world wide estimates of AD projected that there were 24 26 million with dementia and that growth to 423 million by 2020 & 106 million by 2050 Many countries expected to have most impact: growth of population in 60+ anticipated not well represented in early survey work Regions well covered Some * studies Single studies Worldwide Prevalence studies: from Delphi Consensus study of Ferri et al, Lancet 2005, 366 Epidemiological Studies of Dementia Global evidence base expanded since earlier AD projections, the G8 Dementia Summit (2013) focused on the new evidence from China and the sub Saharan African regions Revised projections of AD higher by ~16%: 76 million affected globally in 2020; 135 million by 2050 Population ageing is the main driver of projected increases Global impact of dementia report (December 2013) 5

Epidemiological Studies of Dementia Global evidence base expanded since earlier AD projections, the G8 Dementia Summit (2013) focused on the new evidence from China and the sub Saharan African regions Revised projections of AD higher by ~16%: 76 million affected globally in 2020; 135 million by 2050 Population ageing is the main driver of projected increases Global impact of dementia report (December 2013) Epidemiological Studies of Dementia Global evidence base expanded since earlier AD projections, the G8 Dementia Summit (2013) focused on the new evidence from China and the sub Saharan African regions Revised projections of AD higher by ~16%: 76 million affected globally in 2020; 135 million by 2050 Population ageing is the main driver of projected increases Global impact of dementia report (December 2013) 6

Currently in 2017 55 million ::::::::::::::::::::::::: people :::::::::::::::::::::: with :::::::::::::::::::::: ::: :::::::::::::::::::::: :::::::::::::::::::::: Alzheimer s 6 th leading ::: :::::::::::::::::::::: cause of death :::::::::::::::::::::: :::::::::::::::::::::: :::: :::::::::::::::::::::: ::::::::::::::::::::::::: :::::::::::::::::::::: :::::::::::::::::::::: :::::::::::::::::::::: ::: :::: 259 billion :::::::::::::::::::::: :::::::::::::::::::::: ::: :::: dollars in :::::::::::::::::::::: :::: :::::::::::::::::::: ::::: :::: :::: :::: annual costs >15 million :::: :::::::::::::: unpaid :::: ::::::::::::::::::::::::: :::: caregivers ::::::::::: :::::: ::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::: :::::::::::::::::::::: ::::::::::: ::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::: :::::::::::::: :::::::::::::::: ::::::::::::::::::::: ::::::::::::::::::::: ::::::::::::::: 2017 Alzheimer s Disease Facts and Figures Alzheimer s Association By the Currently year 2050 13854 16 million million ::::::::::::::::::::::::: Americans people :::::::::::::::::::::: with :::::::::::::::::::::: ::: :::::::::::::::::::::: :::::::::::::::::::::: affected Alzheimer s by 6 th leading ::: :::::::::::::::::::::: 2050 cause of death :::::::::::::::::::::: :::::::::::::::::::::: :::: :::::::::::::::::::::: ::::::::::::::::::::::::: :::::::::::::::::::::: :::::::::::::::::::::: :::::::::::::::::::::: ::: :::: 200 11 Trillion billion :::::::::::::::::::::: :::::::::::::::::::::: ::: :::: dollars annually in :::::::::::::::::::::: :::: :::::::::::::::::::: ::::: :::: :::: :::: annual (Alz Assoc, costs 2013 Alz & Dementia 9: >15 million :::: :::::::::::::: 208 45) unpaid :::: ::::::::::::::::::::::::: :::: caregivers ::::::::::: :::::: ::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::::::: ::::::::: :::::::::::::::::::::: ::::::::::: ::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::::: :::::::::::::: :::::::::::::: :::::::::::::::: ::::::::::::::::::::: ::::::::::::::::::::: ::::::::::::::: 2017 Alzheimer s Disease Facts and Figures Alzheimer s Association 7

Delaying onset of dementia by 5 years 53 million fewer Americans Net decrease of 40% (Rand Report 2013 NEJM; & Alz & Dementia 2013 9:208 45) National Alzheimerʹs Project Act (NAPA) January 4, 2011 Enacted Passed unanimously by both houses of Congress Signed into law by President Obama Creates a national strategic plan to address & overcome the escalating crisis of Alzheimer s disease 2013 goal announced to develop treatments to slow progression and prevent onset of AD by 2025 8

National Alzheimerʹs Project Act (NAPA) Congress added $100 million in 2014 to the National Institute on Aging (NIA) portfolio for Alzheimer's research Doubled the $100 milliongoing to the so called BRAIN initiative (Brain Research through Advancing Innovative Neurotechnologies) important for new insights into treatment National Alzheimerʹs Project Act (NAPA) To fully meet the 2025 goal will require $2 billion annually over the next decade in research funding Where's the War on Alzheimer's? As research September 6, 2017 Senate funding lags, cases are increasing with staggering costs TR Reid (wwwaarporg/health/brai health/inforfunding AD research in fiscal 2015/alzheimer researchhtml) proposed a $414 million increase in year 2018 (to $18 billion) 2015 2016 Congress approved additional appropriations to the NIH for AD research Bringing the total to over $14 billion: $365 development of new biomarkers and disease monitoring technologies $928 million would go toward translational research and clinical interventions; $451 million to studying Alzheimer's disease epidemiology; and $98 million to improving how Alzheimer's disease patients are cared for, such as optimizing dosing regimens with existing drugs $31 million would be used to improve resources for researchers including data and tissue repositories; and $354 million to help establish and support research partnerships between the public and private sectors 9

Where we are today Bad News There is no treatment that will allow us to prevent the disease from occurring There is no treatment to stop the disease once it has started Where we are today Good news Considerable progress in: Scientific understanding of the biology of the disease Advances in technology, allowing earlier diagnosis and treatment possibilities Evidence based approaches for lowering risk and promoting healthy cognition Funding opportunities for behavioral sciences to advance translational research 10

Where we are today Bad News There is no treatment that will allow us to prevent the disease from occurring There is no treatment to stop the disease once it has started Good news Considerable progress in: Scientific understanding of the biology of the disease Advances in technology, allowing earlier diagnosis and treatment possibilities Evidence based approaches for lowering risk and promoting healthy cognition Funding opportunities for behavioral sciences to advance translational research OBJECTIVES 1 Discuss reliable diagnosis of Alzheimer s disease across its spectrum; 2 Consider Alzheimer s disease therapeutics and clinical prevention approaches; 3 Conclude with future research and clinical care in Alzheimer s disease & the role of neuropsychology in this context 11

OBJECTIVES 1 Discuss reliable diagnosis of Alzheimer s disease across its spectrum; 2 Consider Alzheimer s disease therapeutics and clinical prevention approaches; 3 Conclude with future research and clinical care in Alzheimer s disease & the role of neuropsychology in this context Chronic Disease Model of AD Neural Substrate of Cognition Pre-clinical (latent pathology- silent) pre MCI cognitive Δ Threshold Mild Cognitive Impairment MCI (AD prodrome stage) AD dementia (Full symptoms/ fxn impaired) Time (age) Welsh-Bohmer, KA Neuropsychol Rev 2008;18(1):70-2 12

Neuropsychological Predictors of Early AD (Backman et al, Neuropsychology, 2005: 19: 520 531) Study Size F/up interval Tests (cog domain) Population Samples Kungsholmen Project (Bäckman et al,1998, 2001; Small 1997) MoVies (Chen et al, 2000, 2001) PAQUID (Fabrigoule et al, 1998) Baltimore Longitudinal Study (BLSA; Grober & Kawas 1997) North Manhattan Aging Project (Jacobs et al, 1995) Canadian Study of Health & Aging (CHSA; Tierney et al 2005) Framingham (Elias et al, 2000) 15 incident dmt 105 nondemented 120 incident dmt 483 controls 16 dmt 1134 controls 20 dmt 60 controls 41 dmt 402 controls 47 dmt 216 controls 109 dmt 1043 controls 3-6 years 15 to 10 years 2 years 3 4 years 1-4 years 5 10 years 2-22 years Word recognition (Episodic Memory) CERAD WLM test Trails A+ B (Episodic Memory & Executive Fx) MMSE, Vis Memory, Veral paired Assoc, Dsy, Similarities (General Cognition) Buscke SRT (Episodic Memory) Naming, Similarities, SRT-immediate (Episodic Memory, abstraction, word finding) ReyAVLT Short term memory (10 yrs) STM, fluency, information (5 yrs) (Verbal memory retrieval) Logical Memory (Recall), Paired Associates, Similarities, COWA (Episodic Memory, abstraction, word finding) Neuropsychological Predictors of Early AD Backman et al, Neuropsychology, 2005: 19: 520 531) Study Size F/up interval Tests (cog domain) Population Samples Kungsholmen Project (Bäckman et al,1998, 2001; Small 1997) MoVies (Chen et al, 2000, 2001) North Manhattan Aging Project (Jacobs et al, 1995) Canadian Study of Health & Aging (CHSA; Tierney et al 2005) Framingham (Elias et al, 2000) 15 incident dmt 105 nondemented 41 dmt 402 controls 47 dmt 216 controls 109 dmt 1043 controls 3-6 years 15 to 10 years 1-4 years 5 10 years 2-22 years Word recognition (Episodic Memory) CERAD WLM test Trails A+ B (Episodic Memory & Executive Fx) 120 incident dmt 483 controls MMSE, Vis Memory, Veral paired Assoc, Dsy, Similarities 2 years (General Cognition) PAQUID MULTIPLE (Fabrigoule et al, COGNITIVE 1998) DEFICITS 16 dmt PREDICTIVE OF LATER AD OUTCOME 1134 controls Buscke SRT Baltimore BIGGEST Longitudinal EFFECTS- Study EPISODIC (BLSA; Grober & Kawas 1997) 20 dmt MEMORY 3 4 years & EXECUTIVE FUNCTION* (Episodic Memory) (*FLEXIBLE THOUGHT & COMPLEX 60 controls DECISION MAKING & ABSTRACTION) Naming, Similarities, SRT-immediate (Episodic Memory, abstraction, word finding) ReyAVLT Short term memory (10 yrs) STM, fluency, information (5 yrs) (Verbal memory retrieval) Logical Memory (Recall), Paired Associates, Similarities, COWA (Episodic Memory, abstraction, word finding) 13

Effect Sizes for Cognitive Domains (Backman et al, Neuropsychology, 2005: 19: 520 531) Domain # Studies Sample Size Controls Cases d (99% CI) O/L% Global cognition Episodic mem Verbal ability Visuospatial Primary Memory Attention Percept Speed Exec Function 35 24 15 9 8 5 4 3 6,509 868 6,694 704 3,625 438 3,159 363 1,567 205 2,969 289 1,274 65 547 166 119* (115-124) 388% 103* (098-108) 421% 079* (0/73-085) 570% 064* (058-071) 618% 000 (-009-009) 100% 062* (055-068) 618% 111* (100-122) 421% 107* (092-121) 421% Effect Sizes for Cognitive Domains (Backman et al, Neuropsychology, 2005: 19: 520 531) Domain # Studies Sample Size Controls Cases d (99% CI) O/L% Global cognition Episodic mem Verbal ability Visuospatial Primary Memory Attention Percept Speed Exec Function 35 24 15 9 8 5 4 3 6,509 868 6,694 704 3,625 438 3,159 363 1,567 205 2,969 289 1,274 65 547 166 119 119* (115-124) 388% 103* (098-108) 421% 079* (0/73-085) 570% 064* (058-071) 618% 000 (-009-009) 100 % 062* (055-068) 618% 111 111* (100-122) 421% 107* (092-121) 421% 107 14

Multiple cognitive impairments predict AD Mayeux et al (2011) Alzheimer s & Dementia 7: 15 34 Edmonds et al, 2015 Alz & Dementia 11: 415 424 0 1 2 3 4 5 6 Episodic memory loss important (eg logical memory, paired associates) but in isolation rarely progresses to dementia 2-3 years later Impairment in expressive language or executive beyond memory loss predictive of conversion to dementia 6% (memory alone) vs 48% (memory +) progressed to AD in 2-3 years Heterogeneity in MCI Diagnosis Edmonds et al (2015) Susceptibility of conventional criteria of MCI diagnosis to false positive error Alz & Dementia, 11:415 424 Measures: Animal fluency, BNT, Trails A, Trails B, AVLT Recall, AVLT Recognition Cutpoint for impair ment Cluster analysis of ADNI MCI cases operationalized CDR=05, impaired delay recall on Log Mem II Story A, MMSE> 23 Neuropsychological data for cases with MCI diagnosis Four subtypes of MCI Dysnomic Dysexecutive Amnestic MCI dx But normal cognitive testing CSF/Genetics dysnomic dysexecutive amnestic normal % low AB 66% 82% 68% 35% % high ptau/low AB 73% 84% 68% 40% % APOE E4 54% 60% 59% 34% 15

Heterogeneity in MCI Diagnosis Edmonds et al (2015) Susceptibility of conventional criteria of MCI diagnosis to false positive error Alz & Dementia, 11:415 424 Measures: Animal fluency, BNT, Trails A, Trails B, AVLT Recall, AVLT Recognition Cutpoint for impair ment Cluster analysis of ADNI MCI cases operationalized CDR=05, impaired delay recall on Log Mem II Story A, MMSE> 23 Neuropsychological data for cases with MCI diagnosis Four subtypes of MCI Dysnomic Dysexecutive Clinical Outcome dysnomic dysexecutive amnestic normal % progressed to dmt 406 556 347 107 Amnestic % reversal to normal 14 10 22 92 MCI dx But normal cognitive testing Bolstering Diagnostic Confidence Longitudinal information declining performance over 18 month Absence of test retest improvement Genetic risk factors linked to AD APOE ɛ4 genotype steeper slope of decline Linked to Aβ on amyloid imaging Pietrzak et al (2015) Trajectories of Memory Decline: Results from the AIBL Study Neurobiology of Aging 36:1231 1238 16

Biomarkers to support a reliable early diagnosis Biomarkers to facilitate an accurate AD diagnosis in life Biological or structural characteristic that can be objectively measured Tracks the disease process or response to therapy Enables assessment of risk or prognosis AD characteristic CNS changes Aß 1 42 peptide total tau protein & phosphorylated tau Neurodegeneration Beta amyloid plaques Frisoni et al (2012) Strategic roadmap for early diagnosis of AD using biomarkers Lance Neurology 16: 661 676 Neurofibrillary Tangles 17

Biomarkers to facilitate AD diagnosis in life Frisoni et al 2012 Lancet Neurol 16: 661 76; Jack et al, 2016 Neurol 87: 539 47 Approach Abnormality Pathology MRI Regional atrophy volume of hippocampus other temporal lobe Tissue loss and neurodegeneration structures PET 18 F fluorodeoxyglucose PET 11 C PiB & fluorinated tracers for amyloid PET 18 F tau PET (eg flortaucipir) uptake post cingulate/ precuneus & temp parietal ctx cor cal reten on cortical retention Glucose hypometabolism & neurodegeneration Deposition of β amyloid Binds 3R/4R PHF tau deposits CSF Aβ42 or Aβ42 Aβ40 Total tau & hyperphosphorylated tau concentra on or ratio concentra on Abnormal metabolism of β amyloid Neuronal damage & accumulation of tau pathology Amyloid deposition precedes AD dementia by 15 years Rowe CC et al (2010) Neurobio of Aging 31: 1275 1283 Australian Imaging, Biomarker, & Lifestyle Study (AIBL) part of worldwide ADNI Obtained C 14 Pittsburgh compound B (PIB) imaging and MRI imagining 177 healthy older controls (HC) 57 MCI 53 mild AD Contrasted deposition of Aβ in HC by age on imaging to Plaques in HC by age autopsy Prevalence of AD dementia by age 18

Amyloid deposition precedes AD dementia by 15 years Rowe CC et al (2010) Neurobio of Aging 31: 1275 1283 Found that in the AIBL population 33% were amyloid positive Increased deposition with age and it was strongly related to e4 The curves for the population prevalence data from epidemiological study behaves very similarly to the postmortem data PIB imaging and postmortem data are completely aligned Suggests that deposition occurs silently, nearly 15 years earlier in HC prior to diagnosis of AD 2011 AD DIAGNOSTIC CRITERIA ALZ & DEMENTIA, 7:263 292 AD DEMENTIA Combine advances in clinical medicine & AD biomarkers PRODROME/ MCI PRE-CLINICAL 19

2011 AD DIAGNOSTIC CRITERIA ALZ & DEMENTIA, 7:263 292 Alzheimer s dementia Mild Cognitive Impairment Cognitive & behavioral impairment that impact ability to function independently Progressive Competing causes Incorporate biomarkers of neuronal injury (MRI/ CSF tau) & of Aβ deposition (CSF/ amyloid imaging) Memory Complaint Cognition objectively impaired with change from a person s baseline Inefficiencies/ no compromise in everyday activities I Incorporate fluid and imaging biomarkers neurodegeneration and Aβ to increase clinical level of certainty (from high, intermediate, not likely, uninformative) Preclinical AD Earliest pathological signs of the disease without obvious clinical symptoms Diagnosis rests entirely on fluid and imaging biomarkers to help stage how close a person is to potentially expressing symptoms Not for use clinically until validated and standardized across laboratories 2011 AD DIAGNOSTIC CRITERIA ALZ & DEMENTIA, 7:263 292 Alzheimer s dementia Mild Cognitive Impairment Cognitive & behavioral impairment that impact ability to function independently Progressive Competing causes Incorporate biomarkers of neuronal injury (MRI/ CSF tau) & of Aβ deposition (CSF/ amyloid imaging) Memory Complaint Cognition objectively impaired with change from a person s baseline Inefficiencies/ no compromise in everyday activities I Incorporate fluid and imaging biomarkers neurodegeneration and Aβ to increase clinical level of certainty (from high, intermediate, not likely, uninformative) Preclinical AD Earliest pathological signs of the disease without obvious clinical symptoms Diagnosis rests entirely on fluid and imaging biomarkers to help stage how close a person is to potentially expressing symptoms Not for use clinically until validated and standardized across laboratories 20

Amyloid PET = CSF Biomarkers for early AD Palmqvist et al (2015) Neurology 85 (14) 1240 1249 Examined the utility of amyloid PET imaging and CSF biomarkers in older adults (n=122) and MCI patients (n=34) who 3 years later develop AD dementia Measures of Aβ 42 /total tau and Aβ 42 / p tau had highest accuracy of the fluid biomarkers Accurate 93 94% Amyloid PET measures had similar level of accuracy Accurate 92 93% No improvement by adding the two tests (imaging & CSF) together, suggesting they are equally accurate 2011 AD DIAGNOSTIC CRITERIA ALZ & DEMENTIA, 7:263 292 Alzheimer s dementia Mild Cognitive Impairment Cognitive & behavioral impairment that impact ability to function independently Progressive Competing causes Incorporate biomarkers of neuronal injury (MRI/ CSF tau) & of Aβ deposition (CSF/ amyloid imaging) Memory Complaint Cognition objectively impaired with change from a person s baseline Inefficiencies/ no compromise in everyday activities I Incorporate fluid and imaging biomarkers of neurodegeneration and Aβ to increase clinical level of certainty ( from high, intermediate, unlikely, uninformative) Preclinical AD Earliest pathological signs of the disease without obvious clinical symptoms Diagnosis rests entirely on fluid and imaging biomarkers to help stage how close a person is to potentially expressing symptoms Not for use clinically until validated and standardized across laboratories 21

When will these biomarkers be ready for presymptomatic use????? Once validated: establishing algorithm of clinical use of an individuals risk and this is not yet clearly established Potential for over diagnosis, No information yet regarding thresholds to apply No information as to when disease might occur imminent, 10 years from now, 20, 30? Work continues in earnest to validate (Jack et al, 2016 Neurology 87: 539 547) Relative temporal ordering when they are most useful & diagnostic thresholds to apply Future applied as therapeutics found and overall clinical impact on morbidity and mortality can be assessed So we can diagnose early then what??? 22

OBJECTIVES 1 Discuss reliable diagnosis of Alzheimer s disease across its spectrum; 2 Consider Alzheimer s disease therapeutics and clinical prevention approaches with an emphasis on our work in TOMMORROW; 3 Conclude with future research and clinical care in Alzheimer s disease & the role of neuropsychology in this context AD Drugs in Development Mangialasche et al Lancet Neurology (2010) 9:702 16 23

Status of AD Drug Development Cummings et al (2014) Alzheimer s disease drug development pipeline: few candidates, frequent failures Alzheimer's Research & Therapy 6:37 Since the last approval in 2003, there have been 413 AD trials were performed One memantine/donepezil combination approved Overall 996% failure In the first quarter of 2017 1 Feb Lilly shutters the last phase 3 study of solanezumab (Aβ monoclonal antibody) 8 Feb Lundbeck terminates development of idalopirdine (5 HT6 agonist) 14 Feb Merck halted study of Verubecestat (BACE1 inhibitor) 28 Feb Accera announced failure of AC 1204 (Ketosis inducing compound) 20 March Selenium and Vitamin E do not prevent dementia (Antioxidants) JAMA Neurol online (April 2017) 24

New Paradigm in AD Drug Development Failure of treatment trials to date (symptomatic treatment and/or disease modification) Stage AD dementia may be too late for effective intervention New research dimensions (focus on pre symptom & early symptom stages of AD) Underlying biology: Failure to effectively address the underlying pathophysiology Ineffective therapy: opportunity for new agents, interventions, & targets Application of biomarkers to facilitate early diagnosis and evaluate efficacy in different stages of drug development Establish new endpoints that establish a clinically meaningful impact of treatments in the disease Development of validated clinical assessment tools sensitive to change in different dimensions in early AD Drug development for prevention, early intervention and disease modification in pre symptomatic/ early symptomatic stages of AD Ongoing AD Prevention Therapeutic Trials DIAN TU Dominantly Inherited Alzheimer s Network Trials Unit (n=438) mutations in APP, PSEN 1 and PSEN 2 agents: solanezumab, gantenerumab, JNJ54861911 API Alzheimer s Prevention Initiative ADAD Columbia kindred (PSEN1 E280A), crenezumab (n=300) Generation homozygous ApoEe4, CAD106 immunotherapy and CNP250 (n=1340) A4 Trials A4: Anti Amyloid treatment in Asymptomatic Alzheimer s (n=1150) amyloid+ PET scan, solanezumab Early: amyloid + by PET or CSF, BACE inhibitor (n=1650) TOMMORROW Program to delay onset of MCI AD (n=3494) Bioenergetic hypothesis to Alzheimer s pathogenesis Low dose pioglitazone (08 mg) Genetically enriched population using a biomarker algorithm of APOE, TOMM40 genotypes & age Source: Clintrialsgov/ J Prev Alz Dis, 4(2) 117 125 (2017) 25

Ongoing AD Prevention Therapeutic Trials DIAN TU Dominantly Inherited Alzheimer s Network Trials Unit (n=438) mutations in APP, PSEN 1 and PSEN 2 agents: solanezumab, gantenerumab, JNJ54861911 API Alzheimer s Prevention Initiative ADAD Columbia kindred (PSEN1 E280A), crenezumab (n=300) Generation homozygous ApoE e4, CAD106 immunotherapy and CNP250 (n=1340) A4 Trials A4: Anti Amyloid treatment in Asymptomatic Alzheimer s (n=1150) amyloid+ PET scan, solanezumab Early: amyloid + by PET or CSF, BACE inhibitor (n=1650) TOMMORROW Program to delay onset of MCI AD (n=3494) Bioenergetic hypothesis to Alzheimer s pathogenesis Low dose pioglitazone (08 mg) Genetically enriched population using a biomarker algorithm of APOE, TOMM40 genotypes & age Source: Clintrialsgov/ J Prev Alz Dis, 4(2) 117 125 (2017) Ongoing AD Prevention Therapeutic Trials DIAN TU Dominantly Inherited Alzheimer s Network Trials Unit (n=438) mutations in APP, PSEN 1 and PSEN 2 Population: agents: solanezumab, gantenerumab, JNJ54861911 autosomal API Alzheimer s Prevention Initiative dominant ADAD Columbia kindred (PSEN1 E280A), crenezumab (n=300) Generation homozygous ApoEe4, CAD106 immunotherapy and CNP250 (n=1340) A4 Trials Target: brain A4: Anti Amyloid treatment in Asymptomatic Alzheimer s (n=1150) amyloid amyloid+ PET scan, solanezumab Early: amyloid + by PET or CSF, BACE inhibitor (n=1650) TOMMORROW Program to delay onset of MCI AD (n=3494) Bioenergetic hypothesis to Alzheimer s pathogenesis Low dose pioglitazone (08 mg) Genetically enriched population using a biomarker algorithm of APOE, TOMM40 genotypes & age Source: Clintrialsgov/ J Prev Alz Dis, 4(2) 117 125 (2017) 26

Ongoing AD Prevention Therapeutic Trials DIAN TU Dominantly Inherited Alzheimer s Network Trials Unit (n=438) mutations in APP, PSEN 1 and PSEN 2 agents: solanezumab, gantenerumab, JNJ54861911 API Alzheimer s Prevention Initiative ADAD Columbia kindred (PSEN1 E280A), crenezumab (n=300) Generation homozygous ApoEe4, CAD106 immunotherapy and CNP250 (n=1340) A4 Trials A4: Anti Amyloid treatment in Asymptomatic Alzheimer s (n=1150) amyloid+ PET scan, solanezumab Early: amyloid + by PET or CSF, BACE inhibitor (n=1650) TOMMORROW Program to delay onset of MCI AD (n=3494) Bioenergetic hypothesis to Alzheimer s pathogenesis Low dose pioglitazone (08 mg) Genetically enriched population using a biomarker algorithm of APOE, TOMM40 genotypes & age Source: Clintrialsgov/ J Prev Alz Dis, 4(2) 117 125 (2017) A Landmark Program to Delay the Onset of MCI Due to Alzheimer s Disease in a Genetically Enriched Population MCI due to AD Low Risk High Risk Placebo Placebo AD 4833 ~5 years ~5 years ~5 years Clinical study planned to follow converters Single pivotal global study across 5 countries on 3continents Screen over 24,000 subjects to randomize ~3,500 subjects, most of whom are in the high genetic risk arm Subjects exposed to at least 4 years of double blind randomized treatment: low dose (08 mg SR) pioglitazone; Primary endpoint: MCI due to AD, event driven study AD, Alzheimer s disease; MCI, mild cognitive impairment 27

TOMMORROW Study: Co Primary Objectives Primary Objectives For biomarker qualification: To qualify the use of the biomarker risk algorithm (BRAA) composed of TOMM40 rs10524523 genotype, APOE genotype, and age for prognosis of the risk of developing MCI due to AD within 5 years For efficacy evaluation of a low dose of pioglitazone: To evaluate the efficacy of pioglitazone to delay the onset of MCI due to AD, in cognitively normal participants who are at high risk for developing MCI due to AD within 5 years, as identified by the biomarker risk algorithm at enrollment Primary Endpoints For biomarker qualification: Time to diagnosis of MCI due to AD for placebo-treated high-risk participants versus placebotreated low-risk participants For efficacy evaluation of a low dose of pioglitazone: Time to diagnosis of MCI due to AD for pioglitazone-treated participants versus placebotreated participants in the high-risk stratum TOMMORROW Study: Co Primary Objectives Primary Objectives For biomarker qualification: To qualify the use of the biomarker risk algorithm (BRAA) composed of TOMM40 rs10524523 genotype, APOE genotype, and age for prognosis of the risk of developing MCI due to AD within 5 years For efficacy evaluation of a low dose of pioglitazone: To evaluate the efficacy of pioglitazone to delay the onset of MCI due to AD, in cognitively normal participants who are at high risk for developing MCI due to AD within 5 years, as identified by the biomarker risk algorithm at enrollment Primary Endpoints For biomarker qualification: Time to diagnosis of MCI due to AD for placebo-treated high-risk participants versus placebotreated low-risk participants For efficacy evaluation of a low dose of pioglitazone: Time to diagnosis of MCI due to AD for pioglitazone-treated participants versus placebotreated participants in the high-risk stratum 28

MCI Due to AD (Primary Endpoint Event) Core clinical criteria (NIA Alz Association criteria, Albert et al 2011) Cognitive concern reflecting a change in cognition reported by participant or informant or clinician (ie, historical or observed evidence of decline over time) Objective evidence of impairment in one or more cognitive domains, typically including memory (ie, formal or bedside testing to establish level of cognitive function in multiple domains) Preservation of independence in functional abilities not demented Etiology of MCI consistent with AD pathophysiological process Core clinical criteria (operationalized) Clinical dementia rating scale score of 05 AND one of the following Fails* at least one of the two memory tests in the cognitive test battery, and the score reflects a decline from baseline Fails two or more of the 12 measures in the cognitive test battery, representing separate cognitive domains, one of which must be memory, and the score reflects a decline from baseline AND Fulfillment of the above criteria on two consecutive examinations, 6 months apart Other potential medical causes are ruled out as proximal cause of the cognitive disorder *Individual test score at or below -15 SD of the demographically corrected normative mean Individual test score at or below -13 SD (10th percentile) of the demographically corrected normative mean MCI Due to AD (Primary Endpoint Event) Core clinical criteria (NIA Alz Association criteria, Albert et al 2011) Cognitive concern reflecting a change in cognition reported by participant or informant or clinician (ie, historical or observed evidence of decline over time) Objective evidence of impairment in one or more cognitive domains, typically including memory (ie, formal or bedside testing to establish level of cognitive function in multiple domains) Preservation of independence in functional abilities not demented Etiology of MCI consistent with AD pathophysiological process Core clinical criteria (operationalized) Clinical dementia rating scale score of 05 AND one of the following Fails* at least one of the two memory tests in the cognitive test battery, and the score reflects a decline from baseline Fails two or more of the 12 measures in the cognitive test battery, representing separate cognitive domains, one of which must be memory, and the score reflects a decline from baseline AND Fulfillment of the above criteria on two consecutive examinations, 6 months apart Other potential medical causes are ruled out as proximal cause of the cognitive disorder *Individual test score at or below -15 SD of the demographically corrected normative mean Individual test score at or below -13 SD (10th percentile) of the demographically corrected normative mean 31

Biomarker algorithm Study Design: Novel Aspects Unique enrichment strategy based on genetic biomarker risk assignment algorithm (BRAA) combining high-risk genotype (APOE and TOMM40 Poly-T allele variants) with age Time to event: MCI due to AD Operationalization of novel clinical endpoint and standardization across 58 global sites Uses comprehensive neuropsychological battery tapping areas not commonly included in clinical trials of AD Therapeutic compound Low-dose pioglitazone: investigation of bioenergetics mechanism Study population Cognitively normal participants enriched to be in the pre-symptomatic to preclinical stages of AD Alzheimer s disease prevention trials completion dates Late onset Alzheimer s disease Autosomal Dominant Alzheimer s disease TOMMORROW API A4 DIAN TU EARLY Generation 2017 2018 2019 2020 2021 2022 2023 2024 2025 Source: Clintrialsgov J Prev Alz Dis, 4(2) 117 125 (2017) 33

Alzheimer s disease prevention trials completion dates Late onset Alzheimer s disease Autosomal Dominant Alzheimer s disease TOMMORROW API A4 DIAN TU EARLY Generation 2017 2018 2019 2020 2021 2022 2023 2024 2025 67 Source: Clintrialsgov J Prev Alz Dis, 4(2) 117 125 (2017) Where we stand now Participants in TOMMORROW have been followed for at least 16 years, many for as long as 3 years, equating to at least 3 6+ cognitive testing endpoints separated by 6 months Some participants have reached 4 years of participation, with 176 now past 42 months Study will undergo the efficacy futility analysis in 2018 Assuming the study passes this futility step, participants will be followed for at least another 2 years until the total number of adjudicated endpoints are reached Implications of TOMMORROW If low-dose pioglitazone proves effective, this would provide a novel therapeutic option to delay MCI symptom onset in vulnerable groups If the genetic algorithm is qualified, this would allow identification of individuals at imminent risk of MCI due to AD within five years The longitudinal neuropsychological data, using commonly accepted clinical tools, will be publically available and will provide important information and insights into emerging incident MCI due to AD in a very large, genetically high-risk population 34

What can we do now until there is a treatment or treatments? ALZHEIMER S DISEASE IS MODIFIABLE Smith, Yaffe et al, (2014) J Alzheimer s Dis: 38, 699 703 All genetic factors of AD known at present account for ~ 1/3 of the risk Non genetic risks factors may include: Societal level: air, water quality, environmental stressors Individual level: lifestyle behaviours smoking, diet, social, cognitive, physical activity Most importantly, MANY non genetic risk factors are modifiable Ridge, PG, Mukherjee, S, Crane, PK, Kauwe, JSK: Alzheimer s disease: analyzing the missing heritability PLoS One 8, e79771 (2013) 35

Lifestyle behavioral Interventions Single domain interventions Diet Physical exercise Cognitive engagement Typically studies of older adults or middle aged adults at risk of AD Short term gains even in MCI and mild AD Longer term gains hinge on continued compliance Multi domain interventions more prevalent (FINGER) Finnish Geriatric Intervention Study to Prevent Cognitive Impairment & Disability (n=591 intervention; n=589 usual care) 2 year randomized study Nutritional guidance, exercise, cognitive training & intensive monitoring of vascular risk factors Roig, M, et al (2013) Neuroscience and Biobehavioral Reviews, 37, 1645 1666; Rebok, GW, et al (2014): Journal of the American Geriatrics Society; 62(1):16 24; Roberts, RO, et al (2015) Neurology 84(18):1854 61, 2015; Kivipelto et al (2013) Alz Dementia 9:657 65 Finnish Geriatric Study to Prevent Dementia Ngandu et al [2015] Lancet 385: 2255 2263) Significant differences at 24 months on primary outcome, a cognitive composite of 14 measures Mean change was very small 020 (intervention) and 016 (control) Significant effects also on BMI, diet, and physical exercise Good adherence at 2 years Seven year dementia outcome data pending Results small but can have large effect on public health 36

When? Timing of Prevention Hsu & Marshall 2017 Current Alzheimer Research 14:426 440 Strategy for prevention: Life course view to a chronic disease To maximize late life outcomes while reducing risk, implement very early, at least in early adulthood Genetics may be used to identify high risk groups to monitor closely Biomarkers incorporated to allow precision in timing and choice of treatment Challenges at societal and individual level to achieve adoption and adherence Where do we go from here? What have all the recent successes and clinical trial missteps taught us? 37

OBJECTIVES 1 Discuss reliable diagnosis of Alzheimer s disease across its spectrum; 2 Consider Alzheimer s disease therapeutics and clinical prevention approaches; 3 Conclude with future research and clinical care in Alzheimer s disease & the role of neuropsychology in this context we have learned that Alzheimer s is a highly complex disease involving dysregulation across multiple neurotransmitter systems & biological pathways over long period of time and just like other complex diseases, there is likely not one answer, one treatment that will prove effective for all 38

Accordingly, the paradigm for finding treatments must change from single drugs for all to personalized approaches that recognize the heterogeneity in the disease & considers appropriately targeted treatments for stage of disease Pulling it Together Levels of Prevention Hsu & Marshall 2017 Current Alzheimer Research 14:426 440 Lifestyle Multi domain Medications Disease Modifying A4/API/DIAN/TOMMORROW ADAPT/GEM/WHIMS FINGER/MAPT/PReDIVA Exercise ADCS EXERT Cognitive training ACTIVE The targeted approaches to AD prevention be multifaceted and vary depending on proximity to symptom onset The most direct approach to AD prevention is a diseasemodifying agent (center) Comes with risk and reserved for those with clear evidence of disease Move out from center, the preventive approach becomes more indirect Single focused lifestyle interventions least direct 39

Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Precision medicine aims at optimizing the effectiveness of disease prevention and therapy by considering an individual s biological makeup Genetic, epigenetic, biomarker status Phenotypic presentation Health factors, lifestyle, & psychosocial characteristics Used successfully in oncology, cardiovascular disease, & infectious diseases Target interventions to specific biological subsets Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Multifactorial diseases require comprehensive systems level approaches to understand the biological organization Genome sequencing (like TOMMORROW algorithmas a basic risk assessment) System level analysis (computational and experimental multiomics) to reveal biological signatures and candidates Tailored, mechanistically targeted interventions customized to the patient 40

Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Multifactorial diseases require comprehensive systems level approaches to understand the biological organization Genome sequencing (like TOMMORROW algorithmas a basic risk assessment) System level analysis (computational and experimental multiomics) to reveal biological signatures and candidates Tailored, mechanistically targeted interventions customized to the patient Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Multifactorial diseases require comprehensive systems level approaches to understand the biological organization Genome sequencing (like TOMMORROW algorithmas a basic risk assessment) System level analysis (computational and experimental multiomics) to reveal biological signatures and candidates Tailored, mechanistically targeted interventions customized to the patient 41

Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Multifactorial diseases require comprehensive systems level approaches to understand the biological organization Genome sequencing (like TOMMORROW algorithmas a basic risk assessment) System level analysis (computational and experimental multi omics) to reveal biological signatures and candidates Tailored, mechanistically targeted interventions customized to the patient Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Challenges Current biomarkers: imaging and CSF biomarkersexpensive & burdensome Ideally there would be a blood based or other less invasive biomarker for diagnosis and tracking plasma tau looking promising Knowledge gap AD field infancy with respect to molecular diagnostics to allow precision therapeutics Need biological signatures like in vitro diagnostics used in oncology or laboratory developed tests & improved cognitive measurement in silent disease Validated, standardized, approved by medicine agencies (FDA, EMA) & guidelines for their use 42

Precision Medicine in AD Prevention Hampel H, et al (2016) JPAD 3(4): 243 259 Opportunities New initiatives in systems biology and precision medicine European Association of Systems Medicine (EASyM) European Prevention of Alzheimer s Disease Consortium (EPAD) Precision Medicine at the NIH Increased research funding in 2016 by $400 million Cautions Ahead in AD Science As we move forward it is important for us to be ever mindful of the gaps in our knowledge of the disease & our assumptions When studies fail, it is important to ask why and to critically evaluate all possible explanations Is the drug engaging the target? Are the endpoints appropriate? Was is the right population, at the right stage of disease, and the right agent? Was the treatment dose optimal? Or is the hypothesis wrong? 43

Hypothetical Model of AD Biomarkers Is it right? Sperling et al Alz & Dementia (2011) 7: 280 92 SUMMARY & CONCLUSIONS 1 Developments in clinical diagnostics using neuropsychological measures complimented by brain imaging and cerebrospinal fluid biomarkers permits the identification of high risk individuals for the imminent expression of Alzheimer s disease Use of these early signatures of disease can be a useful research strategy to enrich study populations for individuals with preclinical disease And the biomarkers and cognitive measures may prove useful endpoints both for gauging therapeutic response and target engagement 44

SUMMARY & CONCLUSIONS 2 AD therapeutic trials have had disappointing failures despite a number of promising agents Failures have been attributed to testing efficacy at end stage disease when the disease is fully entrenched Consequently, trials are now positioned at early stages in the preclinical stage in an effort to delay onset of symptoms and optimize brain health SUMMARY & CONCLUSIONS 3 Treatment strategies may have optimal timing windows with some strategies being effective very early in adulthood Single domain and multi domain lifestyle approaches most effective when neuronal restorative processes supporting brain resilency are in place (middle life) As disease processes are underway, therapeutic strategies aimed at selective AD biological targets needed 45

SUMMARY & CONCLUSIONS 4 Moving forward swiftly for breakthroughs in preventing AD by 2025 will require Collaborations and harmonization of clinical trials in AD to permit comparisons & data mining Interdisciplinary research to understand mechanisms of brain disease Improved neuropsychological measures to track at an individual level decline and response to treatment in silent, preclinical disease Including novel methods such as computerized measures, smartphone apps, wearables and other devices Focused work in public policy & behavioral health to improve life style practices that when implemented very early in the lifespan can improve overall health and brain resiliency We can diagnose AD reliably early in symptomatic disease & there is much we can do about AD 1) Be ambitious about prevention with lifestyle changes, management of sensory loss, depression, social engagement etc 2) Treat what we can treat (HTN,diabetes) 3) Provide cognitive treatments for symptoms 4) Build a care team who can help as you plan for the future 5) Utilize new technologies to optimize function at home 6) Be a part of research 46