Examining APOE ε4 and Longitudinal Vascular Brain Injury: The Strong Heart Study

American Indians have a high population risk for cerebrovascular disease, vascular brain injury (VBI), and dementia. The apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease but is also associated with white matter hyperintensities (WMH) and VBI. However, these association have not been thoroughly examined in the American Indian population. Our objective was to determine whether APOE ε4 carriers exhibited greater longitudinal changes in WMH or if the previously reported null effect from cross-sectional findings extended over time in American Indians.

We analyzed data from a population-based, longitudinal cohort of American Indians aged 64-95 years from the Strong Heart Study recruited from Northern Plains, Southern Plains, and Southwest regions. Magnetic resonance imaging markers included infarcts, lacunes, hemorrhages, and WMH. APOE genotype was determined through serum analysis and dichotomized based on the presence of the ε4 allele. Covariates included age, sex, education, hypertension, diabetes, stroke history, body mass index, low-density lipoprotein cholesterol, and study site. We used Poisson regression for binary VBI outcomes, linear mixed-effects models to assess longitudinal WMH changes, and Cox regression to analyze incident VBI.

The sample size was 395 participants with a mean age of 71.3 (4.7) years and was comprised of 313 non-ε4-carriers and 82 ε4-carriers, predominantly female (70.1%). Cross-sectional analyses indicated no significant associations between APOE ε4 and lacunes (RR=1.03, 95% CI: 0.42-2.57), infarcts (RR =1.28, 95% CI: 0.81-2.02), or hemorrhages (RR = 1.73, 95% CI: 0.60-4.99). Longitudinal analyses revealed no significant associations between APOE ε4 and changes in WMH volume (β = 0.00, 95% CI: -0.02-0.03). APOE ε4 was not associated with overall VBI incidence in fully adjusted models (HR = 2.84, 95% CI: 0.17-48.59).

Our findings echo previous work that APOE e4 does not appear to have specificity as a risk factor WMH in American Indians. Further research in a larger sample size and as well as how modifiable environmental factors might modify the biological effects of APOE ε4 on brain aging in American Indians is required to validate these findings.