Associations of plasma HDL subclasses with incident dementia risk in older adults

Abstract INTRODUCTION Plasma high‐density lipoprotein (HDL) varies in size. We examined the associations between HDL subclasses and their lipid composition and incident dementia risk in older adults. METHODS We included 23,790 United Kingdom (UK) Biobank (UKB) and 147 Atherosclerosis Risk in Communities (ARIC) older adults free of dementia at baseline. HDL subclasses and their lipid composition were characterized using two distinct approaches: Nightingale nuclear magnetic resonance (NMR) spectroscopy in UKB and anion‐exchange chromatography followed by mass spectrometry‐based lipidomics of physically isolated HDL subfractions (AEX‐MS) in ARIC. Cox regression models were used to evaluate the associations, adjusting for covariates. RESULTS In the UKB, Nightingale NMR‐derived plasma small and very large HDL particle and six lipid concentrations (total lipids, triglycerides [TG], phospholipids, free cholesterol, cholesterol ester [CE], total cholesterol) were associated with lower and higher risks of incident dementia, respectively. These associations were likely driven mainly by particle concentration in NMR‐derived small HDL and by both lipid and lipid concentrations in NMR‐derived very large HDL. In the ARIC, total TG in AEX‐defined HDL subfraction 1 (e.g., smaller HDL), total lysophosphatidylcholine (LPC) and phosphatidylethanolamine (PE), and TG in AEX‐defined subfraction 2 (e.g., larger HDL) were associated with a lower incident dementia risk. DISCUSSION Although different HDL subclass characterization and lipid measurement methods made it difficult to compare results across cohorts, HDL subclasses and their lipid compositions were associated with the risk of incident dementia in both cohorts.