Affiliations: [a] Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, USA
| [b] Department of Electrical and Computer Engineering, University of Pittsburgh, Pittsburgh, PA, USA
| [c] Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
| [d] Department of Psychiatry, University of California – San Francisco, San Francisco, CA, USA
| [e] Department of Math, Statistics and Computer Science, University of Illinois at Chicago, Chicago, IL, USA
Correspondence:
[*]
Correspondence to: Alex Leow MD, PhD, School of Public Health/Psychiatric Institute (SPHPI), 1601W. Taylor St., SPHPI MC 912, Chicago, IL 60612, USA. Tel.: +1 626 757 8704;
E-mail: alexleow@alumni.ucla.edu.
Abstract: 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 ɛ4, amyloid-β) 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 ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β= –0.007). Regression modeling including APOE ɛ4 allele carriers (Aβ–) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β= 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 ɛ4 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 ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.
