Apolipoprotein E4 (APOE4) allele is associated with an increased risk for both Alzheimer’s Disease (AD) and cardiovascular disease (CVD). APOE4 association with WMHV (a measure of small vessel vasculopathy) is ambiguous. While APOE4 carriage is associated with greater AD pathology, it remains unclear whether cerebrovascular damage is also associated with APOE4 carriage. The aim of this meta-analysis is to determine whether WMHV is associated with APOE carrier status.

 12 studies from Pubmed and EMBASE were found where data for sample size, age, WMHV, study setting, and WMHV quantification method were extracted from each article. Random effect models were used to estimate raw and standardized mean differences for WMHV in APOE4 carriers and non-carriers in addition to subgroup analyses (clinic and community). Analyses were carried out using the ‘metacont’ function in the ‘meta’ package in R 4.0.3.

The 12 studies yielded a total sample size of 16,738 (e4 carrier n=4,721; e4 non-carrier n=12,017) with an average age of 69.72 years. The primary analysis found no significant difference in WMHV between e4 carriers and non-carriers (95% CI (-0.01, 0.15), p = 0.09) with a moderate level between-study heterogeneity (I2 = 64%, 95% CI (33%, 81%). Subgroup analyses showed a small effect size indicating that APOE4 carriers had a greater WMHV (n = 8, 95% CI (0.02, 0.16), p = 0.008) with moderate heterogeneity (I2 = 55%, 95% CI (1%, 80%). No significant difference in WMHV by APOE4 status was noted among clinic-based studies (n = 3, 95% CI (-0.60, 0.41), p = 0.70).

Our findings show an insignificant difference in WMHV between APOE4 carriers and non-carriers. However, utilized community-based samples showed that WMHV was greater in e4 carriers. This suggests that non-APOE factors have a greater influence on WMHV.