Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology

Alzheimer Dis Assoc Disord. 2021 Jul-Sep;35(3):223-229. doi: 10.1097/WAD.0000000000000442.


Background: The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology.

Methods: This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise.

Results: There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on β-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated β-amyloid for the APOE4 carriers only. There was a significant interaction between non-high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non-high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers.

Conclusions: Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism
  • Apolipoprotein E4 / genetics*
  • Blood Pressure / physiology
  • Brain / pathology*
  • Female
  • Healthy Volunteers / statistics & numerical data*
  • Heart Disease Risk Factors*
  • Humans
  • Male
  • Positron-Emission Tomography


  • Amyloid beta-Peptides
  • Apolipoprotein E4