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Insights in Alzheimer's Disease: Research Updates and Advances

Stay informed with the latest developments in Alzheimer's disease research, including pathogenesis, diagnosis, biomarkers, and treatment updates. Explore the historical background, neurodegenerative disorders, and the impact of dementia on individuals.

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Insights in Alzheimer's Disease: Research Updates and Advances

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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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