Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype

Abstract INTRODUCTION Whether apolipoprotein E's ( APOE ’s) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low‐density lipoprotein [LDL], high‐density lipoprotein [HDL], non‐HDL cholesterol, total‐to‐HDL, LDL‐to‐HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive impairment (OR = 2.38; 95% CI: 1.85 to 3.06) risk were greatest in relation to higher remnant cholesterol levels. Greater cholesterol consumption related to poorer lipids in APOE 4+ compared to APOE 3 carriers. DISCUSSION APOE 4+ carriers consuming more cholesterol had less favorable lipids, which were associated with greater dementia and cognitive impairment risk. Highlights Less favorable serum lipids were associated with higher dementia incidence. Mendelian randomization findings suggest causality between lipids and dementia. Lipid levels in older women may be clinical indicators of dementia risk. APOE 4 carriers had poorest lipid profiles in relation to cholesterol consumption. APOE risk for dementia may be modifiable through lipid management.