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Background: Dysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer's disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+). Method: Multimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μFEMALES = 74.9, and μMALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR > 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Result: Results presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid. Conclusion: We've demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not. Figure. 1. Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance. [ABSTRACT FROM AUTHOR]

Background: Multimodal neuroimaging modalities may improve detection of early brain changes associated with Alzheimer's disease (AD). We investigated cognitively intact middle‐aged individuals to determine whether male and female APOE‐ε4 carriers demonstrate altered connectivity using a novel multimodal connectomics technique to probe excitation‐inhibition balance. Method: For 38 cognitively intact APOE‐ε4 carriers aged 40‐60 (μ=50.8) and 38 age (μ=50.9) and sex‐matched (16M/22F) non‐carriers, imaging included: T1‐weighted MRI, resting‐state fMRI and diffusion‐weighted MRI (Korthauer et al, 2018. NeuroImage, 178, 295‐305). Functional connectomes (rs‐FC), constructed with 80 regions of interest (ROIs) used correlation‐based methods on BOLD activity. The hybrid resting state structural connectomes (rs‐SC), constructed using a recently proposed multimodal connectome technique, leverages statistical mechanics to infer connectome‐level excitation‐inhibition balance (Fortel et al, 2019. MICCAI Conference. 503‐511, Springer). Positive edges in this rs‐SC indicate excitatory relationships between ROI pairs, while negative indicate inhibitory relationships. For each ROI, a hyperexcitation indicator (HI) was defined as the percentage of positive edges. Result: Using rs‐SC and rs‐FC, figure 1 presents a comparison for each sex between group‐averaged HI for ROIs of carriers and non‐carriers. For each sex, we compared carriers and non‐carriers using 2‐sample T‐tests. Functional connectivity shows no significant difference for percentage of positive BOLD correlations for both genders (P > 0.05). By contrast, using rs‐SC, females have a significant increase in HI compared to non‐carriers (P < 0.001), suggesting female APOE‐ε4 carriers have globally disrupted E‐I balance that may confer greater vulnerability to AD neuropathology. Figure 1. Average HI for each ROI computed using the rs‐SC (1A) and rs‐FC (1B). Line x = y is a reference for equal HI between groups. While a strong linear relationship exists between carriers and non‐carriers for both genders using functional connectivity, the HI is comparable. Using rs‐SC, female ε4 carriers show a significant increase in HI compared to non‐carriers. Conclusion: We demonstrated a global shift towards hyperexcitation in a group of cognitively intact female ε4 carriers, less so in the male carriers. Our findings are consistent with known AD sex differences, suggesting that novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not. [ABSTRACT FROM AUTHOR]