Ginkgo biloba for the Prevention of Dementia and Alzheimers Disease The Ginkgo Evaluation of Memory Study GEMS

1. Ginkgo biloba for the Prevention of Dementia and Alzheimer's DiseaseThe Ginkgo Evaluation of Memory Study (GEMS) Steven T. DeKosky, MD for The GEMS Investigators Vice President and Dean University of Virginia School of Medicine Charlottesville, VA

2. Rationale for GEMS Incidence of Alzheimer's doubles every five years past 65 One third of Americans over the age of 85 suffer from some kind of dementia Long-term institutionalization of the patient, and financial and emotional devastation of the family Care of dementia patients > $100 billion/year Currently no approved medication for prevention of dementia Laboratory and animal evidence that Ginkgo might work Powerful antioxidant effects In vitro effects against fibrillization of amyloid

3. Ginkgo biloba One of the oldest known tree species (about 270 million years old) Can live for over 1000 years Ginkgo is used in China as a traditional medicine for a range of conditions: Memory enhancement Asthma Bronchitis Cardiac disease Medicinal extract is from the leaf It is one of the 10 best-selling herbal medications in the United States (2007 sales totaled over $107 million)

4. Overview of GEMS Primary outcome: Determine whether occurrence of dementia (any type) and Alzheimer�s disease specifically is lower for older people with normal memory treated with Ginkgo biloba compared with a placebo Design: Randomized, double-blind, multi-center clinical trial 3,069 persons = 75 years old with normal memory or very mild cognitive impairment (MCI = 10%)

5. Secondary Outcomes All-cause mortality Combined CHD � nonfatal MI, CHD death, coronary revascularization, hospitalized angina Combined CVD � combined CHD, stroke, lower extremity revascularization, treated angina, fatal/ hospitalized/treated CHF, hospitalized or outpatient PAD General cognitive function (change over time) Physical function

6. Secondary Objectives: Subgroups Pre-specified Mild Cognitive Impairment Baseline CHD Apo-E genotype

7. Safety Outcomes Hospitalization for bleeding Gastrointestinal Hemorrhagic Stroke

8. The GEM Study Design

9. Sites in GEMS 5 clinical sites in the United States, all Academic Medical Centers: Johns Hopkins (Hagerstown, MD) University of California, Davis (Sacramento, CA) University of Pittsburgh, (Pittsburgh, PA) Wake Forest University Winston-Salem, NC Greensboro, NC

10. GEM Study Coordination and Oversight

11. Randomized Design of GEMS

12. Inclusion Criteria for GEM Study Age/sex: men and women aged > 75 years English is usual language Willing to identify a �proxy� to help in memory assessment Cognitive Function Criteria: Modified Mini-Mental State (3MS) score > 80 Normal score on the Dementia Questionnaire (DQ) Full Neuropsychological Battery consistent with either normal memory or MCI

13. Major Exclusion Criteria Currently taking the anti-coagulant warfarin or have a history of bleeding disorders Taking medications for treatment of cognitive problems or dementia Participant unwilling to discontinue taking over-the-counter (OTC) Ginkgo biloba for the duration of the study History of or treatment for Parkinson's disease Congestive heart failure with disability Hospitalized for depression within the last year, or history of ECT Use of greater than 400-IU of vitamin E per day

14. Sample Size Assumptions & Statistical Methods Power: 96% to detect 30% reduction, 86% to detect a 25% reduction in risk for primary outcome 2-sided a=.05 Analysis according to �intent to treat� Cumulative event rates � Kaplan-Meier Differences between event curves - Log-rank tests & Cox proportional hazards (PH) model

15. GEMS Visit Components 2-hour cognitive assessment (w/proxy) Depression assessment Medical history including CVD Medication update (prescription & OTC) Functional testing (walking speed) Blood draw for serum marker and genetic testing

16. GEMS Cognitive Test Battery

18. GEMS Design: Dementia Outcome Ascertainment Incident dementia based on: 1. Neuropsychological testing 2. Neurological exam 3. MRI 4. Review and final �diagnosis� according to standardized definitions and by panel of experts in dementia diagnosis

19. GEMS Results:Baseline Characteristics

20. GEMS Results: Baseline Characteristics

21. GEMS Results:Cumulative adherence to assigned study tablets by follow-up visit (excluding death and incident dementia)

22. GEMS Results: Cumulative Dementia Rates by Treatment

23. GEMS ResultsHazard Ratios for Cox Regression Analyses All Dementia and Subtypes of Dementia comparing Ginkgo to placebo

24. GEMS ResultsHazard Ratios for All Dementia and Subtypes of Dementia Those at Baseline with Normal Cognition and MCI

25. GEMS ResultsAdverse Events

26. Overall Conclusion

27. The GEM Study: Other Conclusions Ginkgo biloba is not effective at reducing the incidence of coronary heart disease in persons over age 75 Ginkgo biloba is not effective at reducing the incidence of stroke persons over age 75 Ginkgo biloba is not effective at reducing mortality in persons over age 75

28. The GEM Study: Other Conclusions Ginkgo biloba at 120 mg twice a day does not increase the risk for bleeding in persons over age 75 True for persons taking or not taking aspirin Effect of Ginkgo biloba on bleeding for persons taking warfarin is still not known

29. The GEM Study: Other Conclusions Large numbers of elderly volunteers can be maintained in research studies for prevention trials A variety of models can be attempted to shorten the time of study Shorter evaluations/larger N Less stringent cognitive criteria at baseline (tradeoff is advance of disease and possible effects of drugs earlier) Aggressive use of biomarkers to determine at risk subjects, increase incidence rates, observe biomarker change to determine use as surrogate

30. The GEM Study: Future Plans Use current information to: Improve ability to identify people sooner who are at risk for Alzheimer�s disease Evaluate whether Ginkgo biloba may improve walking ability, depression, cancer risk, etc. Additional testing of some GEM Study volunteers: Help understanding of changes in brain function with age and memory decline Includes brain MRI Scans, limited new memory testing (FDG and PiB-PET scans for Pittsburgh volunteers)

31. The GEM Study: Recommendations Ginkgo biloba should not be used for the prevention of memory loss, Alzheimer�s disease, heart disease or stroke in older people Research like GEMS is critically important if our nation is to implement the most cost-effective use of scarce Medicare dollars

32. Principal Investigators and Functions Cognitive Diagnostic Center (University of Pittsburgh) ST DeKosky MD PI J Saxton PhD O Lopez MD Beth Snitz, PhD Clinical diagnoses, dementia ascertainment, consensus conference Clinical Coordinating Center (Wake Forest) C Furberg, PI J Williamson, CoPI intervention adherence, adverse effects, IRB issues, training, performance monitoring and QC MRI Center (Pitt) Carolyn Meltzer, MD, PhD Data Coordinating Center (Univ. Washington) R. Kronmal, PhD PI A Fitzpatrick, PhD data management, statistical analyses, randomization, tracking participants Clinical Field Centers L Fried MD and Michelle Carlson (Johns Hopkins) G Burke MD PI (Wake Forest) L Kuller MD PI (Pitt) J Robbins MD PI (UC-Davis) Evaluation and follow-up of subjects Blood laboratory (Univ. Vermont) R Tracy PhD PI