LDL cholesterol is associated with higher AD neuropathology burden independent of APOE.

Abstract

<i>APOE</i> is a strong risk factor for Alzheimer's disease (AD) and associated with higher low-density lipoprotein cholesterol (LDL-C) levels. Moreover, LDL-C is associated with the development of clinically ascertained AD; however, whether this association is present with the underlying neuropathological manifestations of AD or whether it is independent of the effect of <i>APOE</i> is unknown and is the focus of this paper. Individuals in the Religious Orders Study/Memory and Ageing Project cohorts with longitudinal measures of blood lipids and detailed autopsies were studied. We modelled the relationship between blood lipids and 12 age-related brain pathologies using a linear mixed model adjusted for potential confounding factors and stratified by <i>APOE</i> genotype with overall significance determined by meta-analysis. Blood lipids considered were LDL-C, high-density lipoprotein cholesterol and triglycerides. Brain pathologies included AD pathology measured by silver staining (Braak stage, a modified Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score and global AD pathology) and immunohistochemistry (beta-amyloid and neurofibrillary tangles) as well as cerebral microinfarct, cerebral macroinfarct, cerebral amyloid angiopathy, cerebral atherosclerosis, hippocampal sclerosis, TDP-43 cytoplasmic inclusions and Lewy bodies. 559 participants (69.1% female) had complete data for analysis. They were followed for a median of 7 years and a median of 3 years prior to dementia onset. LDL-C was associated with all measures of AD neuropathology (neurofibrillary tangles, beta-amyloid, Braak stage, modified CERAD score and global AD pathology) and cerebral amyloid angiopathy independent of <i>APOE</i> after adjusting for age, sex, cholesterol-lowering medication use, body mass index, smoking and education at false discovery rate (FDR) p-value <0.05. These findings implicate LDL-C in the pathophysiology of AD independent of <i>APOE</i> and suggest LDL-C is a modifiable risk factor for AD.