APOE-ε4 risk variant for Alzheimer's disease modifies the association between cognitive performance and cerebral morphology in healthy middle-aged individuals

The APOE-ε4 genotype is the highest genetic risk factor for Alzheimer's disease (AD). In cognitively unimpaired individuals, it has been related to altered brain morphology, function and earlier amyloid beta accumulation. However, its impact on cognitive performance is less evident. Here, we examine the impact of APOE-ε4 allele load in modulating the association between cognitive functioning and brain morphology in middle-aged healthy individuals. A high-resolution structural MRI scan was acquired and episodic memory (EM) as well as executive functions (EFs) were assessed in a sample of 527 middle-aged unimpaired individuals hosting a substantial representation of ε4-homozygous (N = 64). We adopted a voxel-wise unbiased method to assess whether the number of APOE-ε4 alleles significantly modified the associations between gray matter volumes (GMv) and performance in both cognitive domains. Even though the APOE-ε4 allele load did not exert a direct impact on any cognitive measures, it reversed the relationships between GMv and cognitive performance in a highly symmetrical topological pattern. For EM, interactions mapped onto the inferior temporal gyrus and the dorsal anterior cingulate cortex. Regarding EFs, significant interactions were observed for processing speed, working memory, and visuospatial attention in distinct brain regions. These results suggest that APOE-ε4 carriers display a structure-function association corresponding to an older age than their chronological one. Our findings additionally indicate that APOE-ε4 carriers may rely on the integrity of multiple compensatory brain systems in order to preserve their cognitive abilities, possibly due to an incipient neurodegeneration. Overall this study provides novel insights on the mechanisms through which APOE-ε4 posits an increased AD risk.