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Updates in Alzheimer's Disease Research

Updates in Alzheimer's Disease Research. Ozioma Okonkwo, PhD Assistant Professor Department of Medicine UW-Madison School of Medicine and Public Health. Agenda. Dementia Historical primer on Alzheimer’s disease Alzheimer’s disease statistics Update I: Pathogenesis Update II: Diagnosis

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Updates in Alzheimer's Disease Research

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

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

  3. 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

  4. 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

  5. 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

  6. 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”

  7. Historical Primer Courtesy of J. Troncoso

  8. 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

  9. 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

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

  11. 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

  12. 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

  13. 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

  14. Updates III: Biomarkers • “Variables that can be measured in vivo and that indicate specific features of disease-related pathological changes” – Jack et al. 2010

  15. Why CSF? “CSF-signature” of AD: Increased tau (t-tau or p-tau) and decreased Aβ42

  16. 68-year-old healthy normal Normal Normal Normal 68-year-old person with AD Abnormal Abnormal Abnormal Amyloid PET Glucose PET MRI

  17. Updates IV: Treatment Preclinical AD Rx MCI due to AD AD Dementia CognitiveFunction Disease Progression

  18. 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

  19. Updates IV: Treatment Courtesy Alzheimer's Association

  20. Updates IV: Treatment Rx MCI due to AD Preclinical AD AD Dementia CognitiveFunction Disease Progression

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

  22. 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

  23. 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., APOE4) • Enrich population with cases with AD pathology • Imaging and CSF biomarkers • Stratify cases based on biomarker profile or genetic risk

  24. Updates V: Clinical trials http://a4study.org/

  25. 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

  26. 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

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

  28. Physical Activity Physically Active Abnormality threshold Biomarker Level Physically Inactive Years

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

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

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

  32. Preliminary FAB Findings

  33. Preliminary FAB Findings

  34. aeRobic 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

  35. NIA Website for Physical Activity http://go4life.nia.nih.gov/ • General Information • Helpful Tips • Online Coaching • Free Resources • Booklets, CDs

  36. 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

  37. http://adrc.wisc.edu/

  38. Acknowledgements • Funding • NIH Beeson K23 AG045957 (PI: O. Okonkwo) • Alzheimer’s Association (PI: O. Okonkwo) • Extendicare Foundation (PI: O. Okonkwo) • NIH R01AG027161 (WRAP, PI: S. Johnson) • NIH R01AG021155 (PREDICT, PI: S. Johnson) • NIH P50AG033514 (WADRC, PI: S. Asthana) • Wisconsin Registry for Alzheimer's Prevention • Kimberly Diggle Mueller, MS • Rebecca Koscik, PhD • Mark A. Sager, MD • Bruce Hermann, PhD • Sterling C. Johnson, PhD • UW Preventive Cardiology Jean Einerson, MS Carol Mitchell, PhD Claudia Korcarz, DVM James Stein, MD • University of Gothenburg, Sweden Henrik Zetterberg, MD, PhD KajBlennow, MD, PhD • UW Kinesiology Ryan Dougherty, BS Dorothy Edwards, PhD Dane Cook, PhD • UCSF Neurology Dena Dubal, MD, PhD • 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, PhD • Cindy Carlsson, MD, MS • Sterling C. Johnson, PhD • Sanjay Asthana, MD • UW Population Health BurcuDarst, BS Corinne Engelman, PhD Contact: ozioma@medicine.wisc.edu • WRAP & WADRC study participants

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