BACKGROUND: The apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis. METHODS: Postmenopausal women (N = 6 795) from the Womens Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included. We examined associations of APOE status (APOE2+ [ε2/ε2, ε2/ε3], APOE3 [ε3/ε3], and APOE4+ [ε4/ε4, ε3/ε4] carriers) with incidence of T2DM, coronary heart disease, stroke, and total CVD events using Cox regression. CVD outcomes were examined in baseline non-statin users and adjusted for statin initiation over follow-up to account for possible confounding by statins. RESULTS: Among all participants (mean age 66.7 ± 6.5 years, 100% non-Hispanic White), 451 (6.6%) were using statins at baseline. Over the follow-up (mean 14.9 and 16.0 years for T2DM and CVD, respectively), 1 564 participants developed T2DM and 1 578 developed CVD. T2DM incidence did not differ significantly by APOE status (ps ≥ .09). Among non-statin users, APOE4+ had higher incidence of total CVD (hazard ratio [95% confidence interval] = 1.18 [1.02-1.38], p = .03) compared with APOE3 carriers, but risks for coronary heart disease (1.09 [0.87-1.36], p = .47) and stroke (1.14 [0.91-1.44], p = .27) were not significantly elevated when examined individually. CVD outcomes did not differ between APOE2+ and APOE3 carriers (ps ≥ 0.11). CONCLUSIONS: T2DM risk did not differ by APOE status among postmenopausal women, but APOE4+ carriers not using statins had an increased risk of total CVD events.

INTRODUCTION: Whether apolipoprotein Es (APOEs) involvement in lipid metabolism contributes to Alzheimers 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 Womens 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 APOE4+ compared to APOE3 carriers. DISCUSSION: APOE4+ 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. APOE4 carriers had poorest lipid profiles in relation to cholesterol consumption. APOE risk for dementia may be modifiable through lipid management.