Association of APOE alleles and polygenic profiles comprising APOE‐TOMM40‐APOC1 variants with Alzheimer's disease neuroimaging markers

Abstract INTRODUCTION TOMM40 and APOC1 variants can modulate the APOE ‐ ε 4‐related Alzheimer's disease (AD) risk by up to fourfold. We aim to investigate whether the genetic modulation of ε 4‐related AD risk is reflected in brain morphology. METHODS We tested whether 27 magnetic resonance imaging‐derived neuroimaging markers of neurodegeneration (volume and thickness in temporo‐limbic regions) are associated with APOE‐TOMM40‐APOC1 polygenic profiles using the National Alzheimer's Coordinating Center Uniform Data Set linked to the AD Genetic Consortium data. RESULTS All brain regions studied using structural phenotypes were smaller in individuals with AD. The ε 4 allele was associated with smaller limbic (entorhinal, hippocampus, parahippocampus) brain volume and cortical thickness in AD cases than controls. There were significant differences in the associations for the higher‐risk and lower‐risk ε 4‐bearing APOE‐TOMM40‐APOC1 profiles with temporo‐limbic region markers. DISCUSSION The APOE ‐AD heterogeneity may be partly attributed to the modulating role of the TOMM40 and APOC1 genes in the APOE cluster. Highlights The ε 4 allele is associated with smaller values of neuroimaging markers in AD cases. Larger values of neuroimaging markers may protect against AD in the ε 4 carriers. TOMM40 and APOC1 variants differentiate AD risk in the ε 4 carriers. The same variants can differentiate the links between ε 4 and neuroimaging markers.