[O5–05–05]: IMPACT OF <i>APOE</i> GENETIC VARIANT ON BRAIN MORPHOLOGY IN A COHORT OF COGNITIVELY HEALTHY MIDDLE‐AGED INDIVIDUALS WITH ENRICHED GENETIC RISK FOR ALZHEIMER's DISEASE

APOE-ε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). In patients, its presence relates with cognitive symptoms severity and increased hippocampal degeneration. Since AD develops slowly, with a preclinical phase that can last for decades, a critical question is whether healthy individuals with higher genetic risk for AD present early neuroimaging signatures of the disease. However, previous studies investigating the impact of APOE-ε4 on grey matter (GM) volumes in cognitively normal individuals have so far shown inconsistent findings, mainly because of poor representation of the ε4-homozygotes in the surveyed samples. We analyzed regional grey matter (GM) volumes using optimized voxel-based morphometry in a sample of 526 middle-aged healthy individuals hosting an unprecedented number of ε4-homozygotes for a single-site study (254 non-carriers, 207 heterozygotes and 65 homozygotes). Compared to non-carriers, ε4-carriers showed reduced GM volumes in several brain regions including the bilateral hippocampus, caudate, and precuneus. We also detected regions displaying increased volume in ε4-homozygotes compared to both non-carriers and ε4-heterozygotes. Finally, we found a significant interaction between APOE genotype and age in target regions which play a critical role in AD pathophysiology, indicating that APOEstatus impacts on the lifespan trajectories of cortical GM volumes. Our data suggest that APOE-ε4 may exert its liability effect by altering brain morphology already in healthy individuals. These results enhance our understanding of how cortical degeneration may initiate in AD and therefore are insightful for developing targeted strategies, which shall delay the onset or slow-down the progression of the disease. Main effects of APOE genotype on grey matter (GM) volumes in 526 middle-aged healthy adults. A) Mean-centered bar plots showing GM volumetric differences among the five APOE genotype groups. Spatial coordinates are given in the Montral Neurological Institute (MNI) standard space. B) Statistical parametric maps displaying main effects of APOE genotype on GM volumes. The bilateral hippocampus and thalamus are represented in cold and warm colors, respectively. Reduced regional grey matter (GM) volumes in APOE-ε4 carriers compared to non-carriers. A) Mean-centered bar plots of contrast estimates. Compared to non-carriers, ε4-carriers show significantly reduced regional GM volumes in a gene dose-dependent manner. B) Mean-centered bar plots of contrast estimates. Significantly reduced GM volumes in ε4-carriers compared to non-carriers in regions showing no dose-dependent effects. C) Statistical parametric maps of brain regions where ε4-carriers displayed significant volumetric reductions compared to non-carriers (P<0.001). Increased regional grey matter (GM) volumes in APOE-ε4 homozygotes. A) Mean-centered bar plots showing significantly increased regional GM volumes in ε4-homozygotes compared to both heterozygotes and non-carriers. B) Statistical parametric maps of brain regions where ε4-homozygotes display significant volumetric increases reported in (A). Interaction between APOE status and age in determining lifespan trajectories of regional grey matter (GM) volumes. Compared to both non-carriers and heterozygotes, the ε4-homozygotes showed significantly reduced age-related GM volumes in the right hippocampus (A) and right lingual gyrus (B). By contrast, in the left thalamus (C), left temporal pole (D) and right superior frontal cortex (E), the ε4-homozygotes displayed increased age-related GM volumes compared to both non-carriers and heterozygotes.