Apolipoprotein E4 Mediates the Association Between Midlife Dyslipidemia and Cerebral Amyloid in Aging Women

Cerebral amyloid-beta (A beta) plaques are the hallmark biomarker of Alzheimer's disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with A beta accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on A beta. We examined the association between midlife lipids and A beta 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45-57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66-77 years). Imaging was performed in 2012/13 via F-18 Florbetaben positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with A beta, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95%CI 1.08-3.01, p = 0.024), but attenuated on adjustment for apolipoprotein E4 (APOE epsilon 4). A beta risk increased in women with APOE epsilon 4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95%CI 2.94-31.31, p < 0.001), APOE epsilon 4 and LDL >3.3 mmol/L (AdjOR9.00, 95%CI 2.89-28.03, p < 0.001), and APOE epsilon 4 and cholesterol to high-density lipoprotein ratio >= 3.25 (AdjOR8.32, 95%CI 2.32-29.89, p < 0.001). Presence of APOE epsilon 4 and midlife dyslipidemia compounded the risk for A beta deposition, although no independent effect of midlife lipids was found. Lipid-modifying treatment in midlife could mitigate the risk of A beta in women with a genetic predisposition for AD. To better inform prevention, future consideration should be given toward managing dyslipidemia in women carrying the APOE epsilon 4 allele.