Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer's Disease Spectrum

Genes (Basel). 2021 Nov 17;12(11):1805. doi: 10.3390/genes12111805.


Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer's disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32-63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10-6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aβ-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.

Keywords: Alzheimer’s disease; aging; amyloid; cholesterol; polygenic score; tau protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aging / blood
  • Aging / cerebrospinal fluid*
  • Aging / pathology
  • Alzheimer Disease / blood
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Apolipoproteins E / blood
  • Apolipoproteins E / genetics
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid
  • Cholesterol / blood*
  • Humans
  • Middle Aged
  • Multifactorial Inheritance*
  • Peptide Fragments / cerebrospinal fluid*
  • tau Proteins / cerebrospinal fluid*


  • Amyloid beta-Peptides
  • ApoE protein, human
  • Apolipoproteins E
  • Biomarkers
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Cholesterol

Grant support