Alzheimer’s Disease Today and Tomorrow First case reported in 1906 Reported by Alois Alzheimer Patient Augusta D. first treated at 46 years old Paranoia, memory loss, confusion Died in five years Brain stained to show plaques and tangles

Major Pathological Changes in AD Brain shrinkage (atrophy) Neuritic Plaques –altered metabolism of APP –Deposition of beta amyloid Neurofibrillary Tangles –Cytoskeletal pathology [girders and trusses] –Altered metabolism of tau protein Neuronal death in specific brain regions (why some regions and not others?)

Current Status Unclear etiology Progressive course Clinical diagnosis much variability No agreed biomarker Uneven progression Suboptimal Medications

Current Status 5.5 Million currently As many as 16 Million by mid century 10 Million baby boomers Patient with Alzheimer’s cost three times what a similar patient without Alzheimers would cost

Current Status $40 million NIH diagnostics alone Four amyloid imaging reagents in clinical testing This doesn’t count natural history studies

Current Status A diagnosis of AD does not equate with the inability to consent

In vivo Amyloid Imaging with Pittsburgh Compound B (PIB) N S NH 11 CH 3 HO PET Imaging - [ 11 C]6-OH-BTA-1 (PIB) N S N CH 3 CH 3 H 3 C CH Histology - Thioflavin T Amyloid Plaques

Genes and Risk of Alzheimer’s Disease Disease Genes “Deterministic” –rare –monogenic –major effect –little, if any, environmental interaction Risk Genes “Susceptibility” –common –polygenic –minimal effect –environment & other genetic factors act as modifiers

PERFORMANCE Symptomatic Agent Placebo Disease Modifier Placebo Time Rx effect is static over time Time Rx effect increases over time PERFORMANCE Classic AD Trial Designs

Alzheimer’s Disease: Course, Prevention, Treatment Strategies Disease Progression No Disease No Symptoms Early Brain ChangesNoSymptoms AD Brain ChangesMildSymptomsMild, Moderate, or SevereImpairment NormalAD Pre- symptomatic AD Mild Cognitive Impairment SecondaryPreventionTreatmentPrimaryPrevention Intervention ClinicalState BrainPathologicState Identify at-risk Prevent AD Prevent or DelayEmergence Of Symptoms StimulateMemory;Slowprogression Treat cognition Treat behaviors Slow progression Strategies Numbers 5 Mil6 to 10 Mil10 to 60 Mil???