A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank

Alzheimers disease (AD) risk is increased in carriers of the apolipoprotein E (APOE) {varepsilon}4 allele and decreased in {varepsilon}2 allele carriers compared with the {varepsilon}3{varepsilon}3 genotype. The aim of this study was to determine whether: APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE {varepsilon}4 carriers) aged 45-80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. Volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE {varepsilon}4{varepsilon}4 (effect size 0.14 standard deviations [SD]) and {varepsilon}3{varepsilon}4 carriers (effect size 0.04 SD) but no differences in {varepsilon}2 carriers compared with {varepsilon}3{varepsilon}3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE {varepsilon}4{varepsilon}4 carriers (effect sizes around 0.2-0.3 SD) and {varepsilon}3{varepsilon}4 (effect sizes around 0.05 SD) carriers but no differences in {varepsilon}2 carriers compared with the APOE {varepsilon}3{varepsilon}3 genotype. Effects did not differ between men and women. APOE {varepsilon}4 homozygotes appeared to have lower WM integrity specifically at older ages with a potentially steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater "brain age". APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.