Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimers disease

BackgroundSex differences impact Alzheimers 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. ObjectiveExamine how AD risk factors (age, APOE-{varepsilon}4, amyloid-{beta}) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. MethodsIndividuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). ResultsIn absence of AD risk factors (APOE-{varepsilon}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-{varepsilon}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). ConclusionSex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-{varepsilon}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-{varepsilon}4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.