Investigating Sex-Dependent Neural Excitation-Inhibition Imbalances in Alzheimer's Disease Using Multimodal Neuroimaging - PROJECT SUMMARY/ABSTRACT Aligned with the NIA’s 2020-2025 strategic plan, this proposed project advances the NIH’s goals to elucidate Alzheimer's disease (AD) mechanisms, identify neuroimaging markers delineating progression from normal cognitive aging to MCI to early AD, and address biological health disparities by sex (Goals D-2, D-3, and F-4). This proposed study employs a multimodal neuroimaging approach, integrating functional MRI, diffusion- weighted imaging, and amyloid-PET imaging, to uncover sex-dependent imbalances in neural excitation- inhibition related to amyloid pathology and across the cognitive spectrum, including cognitively unimpaired individuals, those with mild cognitive impairment (MCI), and those with AD dementia. Current literature indicates that E/I imbalances, such as epilepsy and subclinical epileptiform activity, are more prevalent in AD and linked to cognitive decline, the AD genetic risk factor APOE-ε4, and amyloid pathology. Specifically, multiple studies show presymptomatic hyperexcitation in at-risk individuals for AD dementia, but despite the known sex differences in AD risk and progression, none have investigated sex-specific E/I imbalances. Our preliminary findings show that this early hyperexcitation is specific to cognitively unimpaired (CU) female APOE-ε4 carriers, suggesting sex-specific neuroimaging biomarkers and therapeutic targets. Indeed, antiseizure medications like levetiracetam have shown promise in restoring E/I balance and improving cognition in AD. Therefore, there is a critical need to better characterize E/I imbalances with respect to sex and AD risk factors and neuropathology to inform future biomarkers and therapeutic approaches. This study will leverage archived data (n = 861) from the Wisconsin Alzheimer’s Disease Research Center (ADRC), Wisconsin Registry for Alzheimer’s Prevention (WRAP), and Wisconsin Alzheimer’s Disease Connectome Project (ADCP) cohorts through the co-sponsor’s affiliation, to better characterize sex-specific E/I imbalance across the dementia spectrum. The proposed project has several novel aspects: 1) a multimodal neuroimaging model developed by our lab that has been published and validated to infer E/I balance with both functional and structural information. This provides a significant advantage over most methods, which sub-optimally infer functional connections between brain regions without empirical structural connectivity; 2) Large sample sizes across the dementia spectrum of cognitively unimpaired, mild cognitive impairment, and AD-dementia; and 3) the use of amyloid-PET to better spatially test the proximity- dependent effect of amyloid on E/I imbalances and in relation to sex. The proposed project will provide training in neuroimaging preprocessing/processing methods, multimodal computational neuroimaging approaches, and clinical experiences to help the applicant achieve their long-term career goals in academic medicine.
