Differential impact of sub‐threshold amyloid‐beta deposition on intra‐ and inter‐network functional connectivity for cognitively normal older adults according to APOE genotype

Abstract

AbstractBackgroundPrevious research has demonstrated that sub‐threshold amyloid‐beta retention is related to cognitive performance, functional brain change, and further amyloid‐beta /tau accumulation. However, few previous studies have examined an effect of APOE genotype on the association between functional connectivity (FC) and memory performance in the earliest stage of Alzheimer’s disease (AD). We aimed to evaluate the difference in intra‐ and inter‐regional FC between cognitive older adults with and without APOE ε4‐allele and examined an impact of intra‐ and inter‐regional FC on memory performance in cognitively intact older adults, according to APOE ε4‐allele status.MethodCognitively normal older adults with and without APOE ε4 allele (carrier, n=32; non‐carrier, n=80) underwent neuropsychological battery, resting‐state functional magnetic resonance imaging (MRI) scans, and positron emission tomography (PET) scans with [18F] flutemetamol. We employed a priori defined regions of interest to investigate the intra‐ and inter‐network FC profiles of default mode network (DMN), central executive network (CEN), and salience network (SN). We evaluated difference in intra‐ and inter‐regional FC via analysis of covariance and examined the intra‐ and inter‐regional FC‐by‐APOE genotype interaction for memory performance by multiple linear regression analysis, adjusting for age, sex, and education years.ResultThere was no significant difference in intra‐ and inter‐regional FC for cognitively intact older adults without amyloid‐beta retention between APOE ε4 non‐carrier and carrier. The inter‐regional FC between DMN and CEN displayed a significant interaction with APOE genotype for word list memory, total memory, and total scores (uncorrected p < 0.001; uncorrected p < 0.005; uncorrected p < 0.05). Cognitively normal older adults with APOE ε4 allele exhibited steeper slope for a positive relationship between the inter‐regional FC and memory performances than those without APOE ε4 allele.ConclusionThe inter‐regional FC between DMN and CEN has a differential impact on memory performances according to the representative AD risk factor, APOE ε4 allele in the earliest phase of AD. These results could contribute to the deeper understanding of the initial pathogenesis of AD.