Quadratic associations between subthreshold amyloid‐beta retention and cortical volume modulated by APOE genotype in cognitively normal older adults

Abstract

AbstractBackgroundA growing body of evidence suggests a deteriorating effect of subthreshold amyloid‐beta (Aβ) accumulation before the onset of clinical symptoms of Alzheimer’s disease (AD). Despite the association between the Aβ‐dependent pathway and the APOE ε4 allele, the modulating impact of this allele on the associations between subthreshold Aβ retention, cortical atrophy, and neuropsychological performance is unclear. This study aimed to explore the differential effect of the APOE ε4 allele on the association between subthreshold Aβ retention, cortical volume, and cognitive performance in cognitively healthy older adults (CN).MethodA total of 112 CN with subthreshold Aβ retention, consisting of 80 APOE ε4 non‐carrier and 32 APOE ε4 carrier, were included in the study. Participants underwent structural magnetic resonance imaging, [18F] flutemetamol (FMM) PET‐CT, and neuropsychological battery. Potential interactions between APOE status and Aβ accumulation were assessed with F‐tests implemented on both linear and quadratic interaction terms, adjusting for age, sex, and education years.ResultWe found a significant interaction between APOE ε4 allele, subthreshold Aβ deposits, cognitive function for cortical volume of predefined brain regions vulnerable to early Aβ retention. In CN with APOE ε4 carrier, regional Aβ retention in frontal, parietal, temporal lobe, and posterior cingulate cortex/precuneus showed a U‐shaped relationship with cortical volumes of superior parietal, fusiform gyrus, and amygdala. Furthermore, cortical volumes of superior, inferior temporal lobe, and parahippocampal gyrus in APOE ε4 carrier displayed a U‐shaped relationship with attention and executive function scores.ConclusionThis study is the first attempt to thoroughly examine the mechanism at play in the earliest phase of Alzheimer’s disease, focusing on the influence of the APOE ε4 allele on the association between subthreshold Aβ retention and cortical volume during the preclinical phase.