Abstract / Summary
Higher high-density lipoprotein cholesterol (HDL-C) is conventionally expected to be protective, yet evidence in Alzheimer’s disease (AD) is inconsistent and may be non-linear; its relationship to amyloid-β (Aβ) oligomerization—an early, neurotoxic step in AD—has not been examined directly in humans. We investigated the association between serum HDL-C and plasma oligomerized Aβ (OAβ) in older adults without dementia. In this cross-sectional analysis of the General Lifestyle and Alzheimer’s Disease (GLAD) cohort, we studied 170 community-dwelling adults aged 65–90 years without dementia (cognitively normal or with mild cognitive impairment). Plasma OAβ was measured using the Multimer Detection System (MDS-OAβ) assay. Multiple linear regression modeled plasma OAβ on serum HDL-C, entered continuously and by category (National Cholesterol Education Program Adult Treatment Panel III scheme: < 50, 50–59, ≥ 60 mg/dL; high-HDL scheme: < 50, 50–79, ≥ 80 mg/dL), unadjusted and fully adjusted for demographic, genetic, vascular, metabolic, and nutritional covariates. Analyses were repeated within diagnostic groups, and effect modification by serum gamma-glutamyl transferase (GGT) was explored. Higher serum HDL-C was independently associated with higher plasma OAβ (adjusted B = 0.004 per mg/dL, 95% CI 0.002 to 0.007, p = 0.002). The association was graded across categories: relative to the < 50 mg/dL reference, plasma OAβ was significantly higher in the ≥ 60 mg/dL group (adjusted B = 0.141, 95% CI 0.049 to 0.234, p = 0.003) and, under the high-HDL scheme, in both the 50–79 mg/dL (B = 0.101, p = 0.014) and ≥ 80 mg/dL (B = 0.195, p = 0.014; n = 12) groups. Associations were similar in cognitively normal and mild cognitive impairment participants. The association was mainly confined to individuals with low GGT. In dementia-free older adults, higher serum HDL-C was independently associated with greater, not lesser, plasma Aβ oligomerization. Because the analysis was cross-sectional, the direction of this association is undetermined. Longitudinal studies incorporating established amyloid biomarkers and direct measures of HDL function are required.