Impact of Sex and Alzheimer’s Disease Risk on Default Mode Network Connectivity

The default mode network (DMN) is a circumscribed network of brain regions active at rest. Alterations to the DMN have been proposed as a potential biomarker for Alzheimer’s disease (AD). We investigated the impact of sex on DMN connectivity in adults at high- (HR) or low-risk (LR) for AD and associations with memory performance and amyloid-beta (AB) deposition.

Ninety-four adults (ages 50-70; 47 women) from the Healthy Aging Translational CoHort (HATCH) were classified as HR or LR for AD based on genetic risk (APOE4 allele) plus hypertension, type 2 diabetes, and/or an AXIS I depressive disorder. Participants underwent 3T MRI/resting-state fMRI, PET (C-11PiB to detect AB), and memory assessments (Face-Name Associative Memory Exam). Regional and intranetwork DMN connectivity were assessed by risk status and sex. Associations with memory and AB levels were examined.

There was a significant sex x risk status interaction on intranetwork connectivity in the DMN (F(2,89) = 7.75, p < .01; HR women (mean + SE; 0.29 + 0.11) LR men (0.24 + 0.02)). Differences in women were driven by connectivity between the posterior cingulate cortex and left (t(34) = 3.76, p < .01) and right (t(45) = 3.37, p < .01) hippocampus. In HR women, decreased intranetwork connectivity was significantly related to worse memory (r = 0.32, p = 0.016) and higher AB (r = -0.39, p = 0.017). In HR men, increased intranetwork connectivity was related to worse memory (r = -0.22, p = 0.08) and higher AB (r = 0.18, p = 0.15) at trend levels. Overall, HR women showed decreased intranetwork connectivity and HR men showed increased intranetwork connectivity relative to their LR counterparts. In each sex, these alterations in connectivity were associated with worse memory performance and higher AB deposition.