Date of Award

August 2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Psychology

First Advisor

Ira Driscoll

Committee Members

Raymond Fleming, Kathleen Hayden, Karyn Frick, Steven Rapp

Keywords

Alzheimer's disease, Apolipoprotein E, Cholesterol, Dementia, Diet, Oxysterols

Abstract

APOE4 confers greatest genetic risk for Alzheimer’s disease (AD), but further investigation is required to identify underlying mechanisms and the potential for risk modification. APOE4 carriers are reportedly at increased risk for dyslipidemia due to impaired cholesterol metabolism compared to non-carriers, which points to the possibility that lipid metabolism may be involved in AD. Dietary cholesterol and fat are known to affect lipid metabolism. Both dietary cholesterol and dyslipidemia appear to influence levels of oxysterols, or oxidized cholesterol, which are in turn associated with AD pathology. The present study examined relations between diet, serum blood lipids, plasma oxysterols, APOE status, and dementia incidence in 5,358 postmenopausal women from the Women’s Health Initiative Memory Study. APOE4 carriers had less favorable blood lipid profiles in relation to higher dietary cholesterol and trans fat intake compared to non-carriers. Survival analysis and Mendelian randomization revealed significantly higher risk for dementia in relation to less favorable blood lipid profiles. APOE3 and APOE4+ carriers trended toward higher levels of oxysterols compared to APOE2+ carriers, though these differences were not statistically significant. Less favorable blood lipid levels were associated with higher levels of 24-hydroxycholesterol (24-OH) and 27-hydroxycholesterol (27-OH). Higher ratios of 24-OH to 27-OH were also associated with greater dementia risk in APOE3 and APOE4+ but not APOE2+ carriers. These findings suggest that dyslipidemia and oxysterols may be involved in APOE4’s conferral of AD risk, as well as potential for risk reduction given APOE’s modification of blood lipids in relation to diet. Further research is needed to determine whether AD risk may be modifiable through dietary or pharmacological interventions.

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