Updates in Alzheimers Disease Research Ozioma Okonkwo Ph

Updates in Alzheimer's Disease Research Ozioma Okonkwo, Ph. D Assistant Professor Department of Medicine UW-Madison School of Medicine and Public Health

Agenda • • • Dementia Historical primer on Alzheimer’s disease statistics Update I: Pathogenesis Update II: Diagnosis Update III: Biomarkers Update IV: Treatment Update V: Clinical trials Summary

Dementia is a Syndrome • Progressive decline in mental abilities that affects a person’s social and occupational functioning – Must be a change from a previous level – Impairs two or more domains of cognition (e. g. , memory and language) – Most dementias caused by a neurodegenerative disease – Some are reversible e. g. , metabolic imbalance

Neurodegenerative Disorders • • Alzheimer’s disease Amyotrophic lateral sclerosis Parkinson’s disease Frontotemporal lobar degeneration − − Behavioral variant frontotemporal dementia Primary progressive aphasia Semantic dementia Corticobasal degeneration • Huntington’s disease • Lewy body disease

Alzheimer’s Disease Dementia • Most common form of dementia • Represents about 80% of all dementias • Pathology can occur alone but most often occurs in combination with other pathologies – Vascular disease – Lewy Body disease • Most studied of dementias due to prevalence

Historical Primer • Alois Alzheimer – Frau Auguste Deter – 51 -yr-old woman – First seen in 1901 – Progressive memory & language loss, paranoia – Died 1906 – Brain autopsy: cortical atrophy, abnormal protein deposits – “Presenile dementia”

Historical Primer Courtesy of J. Troncoso

Updates I: Pathogenesis • Late 60’s, search for neurochemical basis • Motivated by progress in Parkinson’s disease • Biochemical alteration as a guide to rational therapeutics • Mid-70’s, reports of cholinergic abnormalities, especially in basal forebrain – Emerging role of acetylcholine in learning and memory • Cholinergic hypothesis of Alzheimer’s disease

Updates I: Pathogenesis • Seminal 2 -page 1992 Science paper, Hardy & Higgins laid framework for “amyloid cascaded hypothesis” – Aggregation of β-amyloid as plaques is causative agent of AD – Other brain lesions (e. g. , tangles) follow from this initial event • Second tenet refuted by neuropathological data – Tangles precede plaques • First tenet supported by several lines of evidence – Causative genes (early-onset AD) and susceptibility genes (late-onset AD) – Animal studies

Updates I: Pathogenesis • Neuritic plaques • Neurofibrillary tangles • Synaptic and neuronal loss

Updates II: Diagnosis • 1984 report by NINCDS-ADRDA workgroup – – – – Presence of dementia syndrome Deficits in two or more areas of cognition Progressive decline in memory and other cognitive functions No clouding of consciousness Onset between 40 and 90, most often >65 No other brain or systemic diseases could account for syndrome Impairment in ADLs as supportive feature

Updates II: Diagnosis • Two-step process – Syndrome (dementia) Etiology (AD) • Reflects prevailing compartmentalized view – One has AD pathological changes dementia – One lacked such changes cognitively normal • Current view – AD pathological changes and clinical decline begin very gradually – Dementia is last stages of many years of accumulation of pathology – In some cases, path. changes start decades before detectable symptoms

Updates II: Diagnosis • AD has three stages – Preclinical • Long, asymptomatic stage – Prodromal (aka mild cognitive impairment) • Emergence of initial symptoms – Dementia • Symptoms sufficiently severe to produce a dementia • Does away with the 2 -step process • “Alzheimer's disease” as brain pathology vs. clinical syndrome

Updates III: Biomarkers • “Variables that can be measured in vivo and that indicate specific features of diseaserelated pathological changes” – Jack et al. 2010 Neuritic plaques Tangles Neuronal dysfunction/loss Cerebrospinal fluid A 42 Phospho-tau Total tau Brain imaging Amyloid PET (eg Pi. B) Tau PET (eg T 807) Glucose PET, f. MRI, T 1 -MRI

Why CSF? “CSF-signature” of AD: Increased tau (t-tau or p-tau) and decreased Aβ 42

68 -year-old healthy normal l a rm No No 68 -year-old person with AD l a m r o bn A Amyloid PET al m r no b A Glucose PET l a m r o n b A MRI

Updates IV: Treatment Preclinical AD Cognitive Function MCI due to AD Rx AD Dementia Disease Progression

Updates IV: Treatment • Current FDA-approved therapeutics fall into 2 classes • Cholinesterase inhibitors – Donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), and tacrine (Cognex) • NMDA receptor antagonist – Memantine (Namenda) • Symptomatic relief versus disease modifying – 6 -12 month delay in symptom worsening in about 50% of cases

Updates IV: Treatment Generic Brand Approved for Side effects Donepezil Aricept All stages Nausea, vomiting, loss of appetite, increased frequency of bowel movements Galantamine Razadyne Mild to moderate Same as Aricept Memantine Namenda Moderate to severe Headache, constipation, confusion, dizziness Rivastigmine Exelon Mild to moderate Same as Aricept Tacrine Cognex Mild to mdoerate Nausea, vomiting, possible liver damage Courtesy Alzheimer's Association

Updates IV: Treatment Rx Preclinical AD Cognitive Function MCI due to AD AD Dementia Disease Progression

Updates IV: Treatment Cognitive Function Early treatment Dementia threshold Late treatment Time

Updates V: Clinical Trials • Develop disease-modifying therapies • Amyloid-targeted approaches – Reduce production, clearance, aggregation • Tau-based approaches • Other approaches • Inflammation • Oxidative stress • Cholesterol • Overall, findings not overwhelming www. alzforum. org/therapeutics

Updates V: Clinical trials • Reasons for little success – Slow rate of disease progression – Enrolment of persons with non-AD pathology • Pathways to increased success – Enroll those further along (e. g. , memory test scores) – Enroll those with genetic risk (e. g. , APOE 4) – Enrich population with cases with AD pathology • Imaging and CSF biomarkers – Stratify cases based on biomarker profile or genetic risk

Updates V: Clinical trials http: //a 4 study. org/

Summary • Pathogenesis – Cholinergic hypothesis, amyloid hypothesis • Diagnosis – AD as brain disease with 3 phases • Biomarkers – Neuroimaging, cerebrospinal fluid • Treatment – Early treatment with disease-modifying agents • Clinical trials – Development of disease-modifying therapeutics

Summary • Cure for AD still in (hopefully, not too distant) future • Meanwhile, attention to modifiable factors – Diet – Cardiovascular health – Social habits – Physical exercise – Cognitive stimulation – Head trauma

Physical Activity • Question: does engagement in physical activity attenuate age-associated alterations in core AD biomarkers

Biomarker Level Physical Activity Physically Active Abnormality threshold Physically Inactive Years

Physical Activity Active=individuals who meet AHA guidelines of 30 min of moderate exercise for 5 days/week

Physical Activity Active=individuals who meet AHA guidelines of 30 min of moderate exercise for 5 days/week

Fitness, Aging, and the Brain (FAB) Study • Aerobic fitness and AD biomarkers Graded Exercise Test Actigraph Other Assessments • • CHAMPS IPAQ Cognitive battery MRI FDG &Pi. B PET CSF sampling Blood assays Genotyping Current N=111 Target N=250

Preliminary FAB Findings

Preliminary FAB Findings

ae. Robic Exercise And Cognitive Health (REACH) • Alzheimer's Association – Randomized Controlled Trial – Test effect of structured aerobic exercise on brain health, cognitive function, and mood – 2 exercise groups • Have positive FH – Work out 3 -4 days/week for ~50 minutes each time – 26 weeks total duration

NIA Website for Physical Activity http: //go 4 life. nia. nih. gov/ – − − − General Information Helpful Tips Online Coaching Free Resources • Booklets, CDs

Resource created as part of the National Plan to Address Alzheimer's Disease to increase public awareness and connect patients and their caregivers with important resources

http: //adrc. wisc. edu/

§ Funding Acknowledgements NIH Beeson K 23 AG 045957 (PI: O. Okonkwo) Alzheimer’s Association (PI: O. Okonkwo) Extendicare Foundation (PI: O. Okonkwo) NIH R 01 AG 027161 (WRAP, PI: S. Johnson) NIH R 01 AG 021155 (PREDICT, PI: S. Johnson) NIH P 50 AG 033514 (WADRC, PI: S. Asthana) § Wisconsin ADRC Stephanie Schultz, BS Liz Boots, BS Taylor Kirby Lena Law Sherman Yu Michelle Berning Jennifer Oh, BS Chuck Illingworth, MS Amy Hawley, BS Barbara B. Bendlin, Ph. D Cindy Carlsson, MD, MS Sterling C. Johnson, Ph. D Sanjay Asthana, MD § UW Population Health Burcu Darst, BS Corinne Engelman, Ph. D § WRAP & WADRC study participants § Wisconsin Registry for Alzheimer's Prevention Kimberly Diggle Mueller, MS Rebecca Koscik, Ph. D Mark A. Sager, MD Bruce Hermann, Ph. D Sterling C. Johnson, Ph. D § UW Preventive Cardiology Jean Einerson, MS Carol Mitchell, Ph. D Claudia Korcarz, DVM James Stein, MD § UW Kinesiology Ryan Dougherty, BS Dorothy Edwards, Ph. D Dane Cook, Ph. D § University of Gothenburg, Sweden Henrik Zetterberg, MD, Ph. D Kaj Blennow, MD, Ph. D § UCSF Neurology Dena Dubal, MD, Ph. D Contact: ozioma@medicine. wisc. edu