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

2. 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

3. Red-yellow = diff small-diff big Mild AD MMSE 20-26 Single domain amnestic -Forgetting where we put things -Forgetting appointments -Repeatiing questions or conversations Multidomain Z score <-2

4. 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

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

6. APP story Mendelian genetics

7. Amyloid hypothesis

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

9. 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

10. Linkage Chr 14 Chr 1

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

12. Genetics proves it is heterogeneous

13. 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

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

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

16. Alzheimer’s disease model: induced pluripotent stem cells

17. 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

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

19. 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