APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression

Abstract

The apolipoprotein E (<i>APOE</i>) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between <i>APOE</i> ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), <i>APOE</i> messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau₁₈₁). Three hundred fifty participants underwent imaging, and 270 had ptau₁₈₁. We used computational models to evaluate the main effect of <i>APOE</i> ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau₁₈₁. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, <i>APOE</i> ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau₁₈₁. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high <i>APOE</i> mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of <i>APOE</i> genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.