1. CL Ropp 1, SL Tyas 1, KP Riley 2, KS SantaCruz 3 1 University of Waterloo, 2 University of Kentucky, 3 University of Minnesota March 29, 2011 The Impact of Brain Infarcts on Dementia Varies by Apolipoprotein E and Educational Status

2. Brain Infarcts & Alzheimer’s Disease  The clinical expression of Alzheimer’s disease (AD) may be influenced by the presence of brain infarcts  Not all individuals with brain infarcts, however, experience dementia

3. Established Risk Factors for AD  Apolipoprotein E (ApoE) status  the ApoE-e4 allele  Educational level  Low educational attainment

4. Research Aim To examine if the influence of brain infarcts on AD and dementia varies by ApoE and educational status

5. Methods - Sample  Data Source: The Nun Study  678 agreed to participate  Annual cognitive and physical assessments  Access to convent archives  Brain donation after death  At the time of this study, 484 participants had died and had pathologic assessment for AD and brain infarcts

6. Methods - Measures  Outcomes:  Dementia  CERAD battery of neuropsychological tests and impaired activities of daily living  AD Pathology  CERAD (probable/definite) or NIA-RI (intermediate/high likelihood) criteria  Alzheimer’s Disease  Both dementia and AD pathology (CERAD/NIA-RI)

7. Methods - Measures  Exposure:  Brain infarcts  Any large or lacunar infarcts visible to the naked eye at gross pathologic assessment  Modifiers:  ApoE and educational status

8. Methods - Analysis  Descriptive  Chi-square tests and t-tests  Multivariate  Logistic regression  Predictor: brain infarcts  Outcomes: dementia, AD (various definitions)  Adjusted by age, ApoE status, and education  Stratified by ApoE status or education

9. Table 1. Association of brain infarcts with dementia, AD, and AD pathology Brain infarcts Unadjusted OR95% CI Adjusted OR 1 95% CI Dementia (n=463) 2.081.42-3.041.901.26-2.86 Bolded value indicate significance 1 Adjusted for ApoE, educational level, and age at death

10. Table 2. Association of brain infarcts with dementia, stratified by ApoE status Dementia Adjusted OR 1 95% CI ApoE-e2 (n=60)6.531.50-28.38 ApoE-e3 (n=286)1.510.91-2.50 ApoE-e4 (n=117)2.330.99-5.47 Bolded values indicate significance 1 Adjusted for educational level and age at death

11. Table 3. Association of brain infarcts with dementia, stratified by educational level Dementia Adjusted OR 1 95% CI <=High school (n=80)1.650.58-4.70 Bachelor’s (n=196)1.720.93-3.19 >=Master’s (n=187)2.351.22-4.55 Bolded values indicate significance 1 Adjusted for ApoE and age at last cognitive assessment

12. Conclusions  Brain infarcts significantly increased the risk of dementia, particularly among low- risk ApoE and educational subgroups  Brain infarcts were not significantly associated with AD pathology or combined AD pathology/dementia outcome

13. Conclusions  Impact of infarcts seems to be driven by their association with clinical symptoms of dementia rather than AD pathology  The greater predictive power of infarcts within low-risk subgroups raises questions about the interplay of neuropathology, risk factors and brain reserve

14. Acknowledgements  School Sisters of Notre Dame religious congregation  Funding for the Nun Study at the University of Kentucky: NIA 5R01AG09862, K04AG00553, P50AG05144; and the Kleberg Foundation  Funding for this project at the University of Waterloo: Alzheimer’s Association grant NIRG 05- 14562  University of Minnesota, home of the Nun Study