Differences in Grey Matter Concentrations and Functional Connectivity between Young Carriers and Non-Carriers of the APOE ε4 Genotype

<b>Background</b>: The pathophysiology of Alzheimer's disease (AD) may begin developing years or even decades prior to the manifestation of its first symptoms. The APOE ε4 genotype is a prominent genetic risk for AD that has been found to be associated with brain changes across the lifespan since early adulthood. Thus, studying brain changes that may occur in young adults with an APOE ε4 status is highly relevant. <b>Objective</b>: Examine potential differences in grey matter (GM) and functional connectivity (FC) in brains of cognitively healthy young APOE ε4 carriers and non-carriers, denoted here as ε4(+) and ε4(-), respectively. <b>Methods</b>: Three Tesla magnetic resonance imaging (MRI) brain scans were acquired from cognitively healthy young participants aged approximately 20 years (n = 151). Voxel-based morphometry (VBM) analysis was employed to identify potential structural differences in GM between ε4(+) and ε4(-). In a subsequent seed-based connectivity (SBC) analysis, brain regions that structurally differed in the VBM analysis were considered as seeds and correlated with all the remaining voxels across the brains to then measure the differences in FC between groups. <b>Results</b>: The VBM analysis suggested that ε4(+) (n = 28) had greater GM densities relative to ε4(-) (n = 123) in the left hippocampus and the left posterior insula (p_uncorr < 0.001). However, the effect did not survive the correction for multiple comparisons, suggesting minimal structural differences in this age range. In contrast, the SBC analysis indicated that ε4(+) exhibited significantly decreased FC between the left hippocampus and areas of the left middle temporal gyrus (n = 27) compared to ε4(-) (n = 102). These results remained significant after multiple comparisons (p_FDR < 0.05). Lastly, no statistically significant differences in FC between groups were observed for the left insular seed (p_FDR > 0.05). <b>Discussion</b>: These results suggest early structural and functional brain changes associated with the APOE ε4 genotype on young adults. Yet, they must be cautiously interpreted and contrasted with both older adults with genetic risk for AD and patients diagnosed with AD.