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

Aliza P Wingo; Selina M Vattathil; Jiaqi Liu; Wen Fan; David J Cutler; Allan I Levey; Julie A Schneider; David A Bennett; Thomas S Wingo

doi:10.1136/jnnp-2021-328164

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

J Neurol Neurosurg Psychiatry. 2022 Jun 30;93(9):930-938. doi: 10.1136/jnnp-2021-328164. Online ahead of print.

Authors

Aliza P Wingo^{1

2}, Selina M Vattathil³, Jiaqi Liu³, Wen Fan³, David J Cutler⁴, Allan I Levey^{3

5}, Julie A Schneider^{6

7}, David A Bennett⁷, Thomas S Wingo^{8

4

5}

Affiliations

¹ Division of Mental Health, Atlanta VA Medical Center, Decatur, Georgia, USA.
² Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia, USA.
³ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
⁴ Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁵ Goizueta Alzheimer's Disease Center, Emory University School of Medicine, Atlanta, GA, USA.
⁶ Departments of Pathology and Neurological Science, Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois, USA.
⁷ Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois, USA.
⁸ Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA thomas.wingo@emory.edu.

Abstract

Objective: APOE 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 APOE is unknown and is the focus of this paper.

Methods: 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 APOE 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.

Results: 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 APOE after adjusting for age, sex, cholesterol-lowering medication use, body mass index, smoking and education at false discovery rate (FDR) p-value <0.05.

Conclusions: These findings implicate LDL-C in the pathophysiology of AD independent of APOE and suggest LDL-C is a modifiable risk factor for AD.

Keywords: ALZHEIMER'S DISEASE; CHOLESTEROL; DEMENTIA; GENETICS; NEUROPATHOLOGY.

Abstract

Grants and funding