Differences in Alzheimer's Disease-Related Pathology Profiles Across Apolipoprotein Groups

The apolipoprotein (APOE) e4 allele is a risk factor for Alzheimer's disease (AD), whereas the e2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype and results are inconsistent for those with an e2 allele. Alzheimer's disease neuroimaging participants were divided into 1 of 4 APOE allele profiles (E4 = e4e4 or e3e4; E2 = e2e2 or e2e3; E3 = e3e3; or E24 = e2e4). Linear mixed models examined the relationship between APOE profiles and brain changes (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures), while controlling for age, sex, education, and diagnostic status at baseline and over time. APOE e4 was associated with increased pathology, whereas e2 positivity is associated with reduced baseline and lower accumulation of pathologies and neurodegeneration. APOE e2e4 was similar to e4 (increased neurodegeneration) but with a slower rate of change. The strong associations observed between APOE and pathology show the importance of how genetic factors influence structural brain changes. These findings suggest that e2e4 genotype is related to increased declines associated with the e4 as opposed to the protective effects of the e2. These findings have important implications for initiating treatments and interventions. Given that people with the e2e4 genotype can expect to have increased atrophy, they should be considered (alongside those with an e4) in targeted interventions to reduce brain changes that occur with AD.