Longitudinal excitation-inhibition balance altered by sex and APOE-ε4

Neuronal hyperexcitation affects memory and neural processing across the Alzheimer's disease (AD) cognitive continuum. Levetiracetam, an antiepileptic, shows promise in improving cognitive impairment by restoring the neural excitation/inhibition balance in AD patients. We previously identified a hyper-excitable phenotype in cognitively unimpaired female APOE-ε4 carriers relative to male counterparts cross-sectionally. This sex difference lacks longitudinal validation; however, clarifying the vulnerability of female ε4-carriers could better inform antiepileptic treatment efficacy. Here, we investigated this sex-by-ε4 interaction using a longitudinal design. We used resting-state fMRI and diffusion tensor imaging collected longitudinally from 106 participants who were cognitively unimpaired for at least one scan event but may have been assessed to have clinical dementia ratings corresponding to early mild cognitive impairment over time. By including scan events where participants transitioned to mild cognitive impairment, we modeled the trajectory of the whole-brain excitation-inhibition ratio throughout the preclinical cognitively healthy continuum and extended to early impairment. A linear mixed model revealed a significant three-way interaction among sex, ε4-status, and time, with female ε4-carriers showing a significant hyper-excitable trajectory. These findings suggest a possible pathway for preventative therapy targeting preclinical hyperexcitation in female ε4-carriers.