Disrupted Excitation-Inhibition Balance in Cognitively Normal Individuals at Risk of Alzheimer's Disease

Background: Sex differences impact Alzheimer's disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. Objective: Examine how AD risk factors (age, APOE epsilon 4, amyloid-beta) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. Methods: Individuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). Results: In absence of AD risk factors (APOE epsilon 4/A beta+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, beta = -0.007). Regression modeling including APOE epsilon 4 allele carriers (A beta-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, beta = 0.014), persisting with inclusion of A beta+ individuals (p = 0.012, beta = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p < 0.05). Conclusions: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE epsilon 4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE epsilon 4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.