Effects of amyloid and APOE4 on medial temporal lobe subregions in cognitively unimpaired elderly

Abstract

AbstractMedial temporal lobe (MTL) sub-structures are differentially affected in early Alzheimer’s disease (AD), with a specific involvement of the entorhinal cortex (ERC), the perirhinal cortex (PRC) and CA1. However, the impact of amyloid (Aβ) pathology and APOE ε4 on MTL subregional atrophy remains relatively unknown. Our aim was to uncover these effects to further our understanding of the mechanisms underlying MTL atrophy in a population at-risk for AD.We used baseline data from 130 unimpaired older adults (mean age: 68.9 ± 3.8 years) from the Age-Well randomized controlled trial for whom high-resolution structural MRI (T2-weighted; 0.4×0.4×2.5mm3), amyloid-PET (Florbetapir) and APOE genotype were available. Participants were dichotomized into amyloid positive (Aβ+, n=27) and negative (Aβ-, n=103), and APOE ε4 carrier (ε4+, n=35) and non-carriers (ε4-, n=95). Hippocampal subfield (CA1, CA2, CA3, dentate gyrus [DG], subiculum [SUB]) and extra-hippocampal region (ERC, Brodmann area [BA] 35 and 36, and parahippocampal cortex [PHC]) volumes were estimated using ASHS and normalized by total intracranial volume. For each subregion, group comparisons were performed (Aβ+ vs Aβ- and ε4+ vs ε4-) using ANCOVAs, including age, sex and education as covariates. Interactions with age (i.e., Aβ status * age and APOE ε4 status * age) were also investigated for each subregion.No significant differences were observed between Aβ+ and Aβ-, nor between ε4+ and ε4-. However, a significant Aβ status * age interaction were observed for CA1 (p<0.05), where volumes were negatively associated with age in the Aβ+ group only. In addition, significant APOE ε4 status * age interactions were found for CA1, SUB, ERC, DG and the whole hippocampus (p<0.05), where volumes were negatively associated with age in the ε4+ group only.Overall, our analyses showed that both Aβ and APOE ε4 status interact with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOE ε4 status mediated the effects of age on other subregions (SUB, ERC, DG), suggesting a more important contribution of APOE ε4 than amyloid to MTL atrophy in cognitively unimpaired population. These results are particularly important to develop MRI-based biomarkers to detect early AD and further our understanding of the mechanisms underlying MTL atrophy.