Sex-Specific Entorhinal Cortex Functional Connectivity in Cognitively Normal Older Adults with Amyloid-β Pathology

Abstract

Sex and apolipoprotein E (APOE) genotype have been shown to influence the risk and progression of Alzheimer's disease (AD). However, the impact of these factors on the functional connectivity of the entorhinal cortex (ERC) in clinically unpaired older adults (CUOA) with amyloid-β (Aβ +) pathology remains unclear. A total of 1022 cognitively normal older adults with Aβ + (603 females and 586 APOE ε4 +) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were included in this study. The 2 × 2 (gender, 2 APOE genotypes) analysis of covariance was performed to compare the demographic information, cognitive performance, and volumetric MRI data among these groups. Voxel-wise comparisons of bilateral ERC functional connectivity (FC) were conducted, and partial correlation analyses were used to explore the associations between cognitive performance and ERC-FC strength. We found that the APOE genotype influenced ERC functional connectivity mainly in the sensorimotor network (SMN). Males exhibited higher ERC-FC in the salience network (SN), while females displayed higher ERC-FC in the default mode network (DMN), executive control network (ECN), and reward network. The interplay of sex and APOE genotype on ERC-FC was observed in the SMN and cerebellar lobe. The ERC-FC was associated with executive function and memory performance in individuals with CUOA-Aβ + . Our findings provide evidence of sex-specific ERC functional connectivity compensation mechanism in cognitively normal older adults with Aβ + pathology. This study may contribute to a better understanding of the mechanisms underlying the early stages of AD and may help develop personalized interventions in preclinical AD.

Keywords: Alzheimer’s disease; Amyloid-beta; Entorhinal cortex; Functional connectivity; Sex Difference.

Fig. 1

The main effect of sex and APOE genotype on ERC-FC network (p < 0.005, α < 0.01, GRF correction). The brain regions show the significant APOE genotype effect (A) and sex effect (B) on the ERC-FC network. For the sex effect on the ERC-FC network, the blue text indicates that male showed higher ERC-FC, while red text indicates that female showed higher ERC-FC. Color bar means the F value. Abbreviations: ERC-FC, entorhinal cortex functional connectivity; vmPFC, ventromedial prefrontal cortex; TP, temporal pole; PosC, postcentral gyrus; SPL, superior parietal lobule; dmPFC, dorsomedial prefrontal cortex; dlPFC, dorsolateral prefrontal cortex; SMG, supramarginal gyrus; PCU, precuneus; PreC, precentral gyrus; SMA, supplemental area

Fig. 2

Functional annotation of Sex special ERC-FC network. Up, the word cloud of the top 50 terms associated with sex special ERC-FC network. The font sizes of the terms represented the correlation coefficients. Down, the top 10 highest significant terms associated with sex special ERC-FC maps. The coordinate values represent correlation coefficients between sex special ERC-FC maps and activation values of behavioral terms from the Neurosynth

Fig. 3

The interactive effect of APOE genotype and sex on the ERC-FC network (p < 0.005, α < 0.01, GFR corrected). A For the left ERC-FC network, the APOE ε4 + individuals exhibited greater sex difference on left PoSc/SPL. B For the right ERC-FC network, the APOE ε3 + individuals exhibited greater sex difference on the left pCbl. Color bar means the F value. Abbreviations: ERC-FC, entorhinal cortex functional connectivity; PosC, postcentral gyrus; SPL, superior parietal lobule; pCbl, posterior cerebellar lobe

Fig. 4

The relationships between ERC volume/ERC-FC and cognitive performance in Aβ positive older. The partial correlation analyses showed that the cognitive performance was significantly associated with the right ERC-FC network, including dlPFC, PreC, SMA insula and TP, and the right ERC volume. Abbreviations: ERC-FC, entorhinal cortex functional connectivity; PACC, preclinical Alzheimer’s cognitive composite; FCSRT, free and cued selective reminding test; R, right hemisphere; L, left hemisphere; TP, temporal pole; PosC, postcentral gyrus; dlPFC, dorsolateral prefrontal cortex; PreC, precentral gyrus; SMA, supplemental area