Aging, Memory and Alzheimer’s Disease Kinga Szigeti, MD, PhD

Aging and Alzheimer’s disease The biggest challenge in AD: it is superimposed on normal aging Insidious onset No blood test; diagnosis is putting a puzzle together Major Public Health Problem

Red-yellow = diff small-diff big Mild AD MMSE Single domain amnestic -Forgetting where we put things -Forgetting appointments -Repeatiing questions or conversations Multidomain Z score <-2

Symptoms late in the disease: cells are damaged We cannot recover nerve cells; goal is to prevent We need biomarkers before the symptoms start PET metabolism and amyloid imaging

Alzheimer disease as a model of complex genetics Not two patients are exactly alike

APP story Mendelian genetics

Amyloid hypothesis

Linkage Trisomy 21 Partial trisomy 21 not including APP-no AD

Candidate gene: APP Precursor protein to amyloid in AD brain Mutations found Disease and mutation went together within families Interestingly some of these mutations affect sites where gamma cleavage occurs

Linkage Chr 14 Chr 1

Amyloid hypothesis: genetic confirmation D Mutations in APP regulatory sequences 40 and 42 APP PSEN1 PSEN2

Genetics proves it is heterogeneous

Research at the University at Buffalo Copy number variation Pieces of chromosomes (genetic material) Missing or in extra copies Olfactory receptor association with AD age at onset

Research at the University at Buffalo Deletion upstream from CREB1 association with AD

CHRFAM7A association with AD Raminathan et al,PlosOne Namenda might work better is this group

Alzheimer’s disease model: induced pluripotent stem cells

The goal: prevention Age 65 well visit/ part of the prevention panel Primary care physician asks about memory issues Screening memory test Blood test for genetic risk factors (gene chip) Assess family history of dementia Then risk stratification: Low riskMonitor Intermediate riskConsider amyloid imaging then Rx High RiskAmyloid imaging then Rx

The goal: personalized treatment If memory problem is present: Clinical workup Gene chip to determine which drugs work best

Until we have the breakthrough: ADMDC patient care Diagnose early Modify risk factors to slow progression Treat to change slope of decline Buys us time Gives years of close to normal life