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bioRxiv · 10.64898/2025.12.16.693545

Genetic Interaction of APOE-E-4 and PICALM rs3851179 is Associated With Dynamic Functional Connectivity in Healthy Middle-Aged Adults at Risk for Alzheimer's Disease

Dharia, S. Y.·Valderrama, C. E.·Liu, Q.·Smith, S. D.
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Abstract

ObjectiveThis study investigates whether dynamic functional connectivity (dFC) dwell-time patterns derived from resting-state fMRI (rs-fMRI) can distinguish Alzheimers disease (AD) genetic risk profiles, specifically the APOE-{varepsilon}4 (A+) and PICALM rs3851179 (P+) variants, in cognitively healthy, middle-aged adults. ApproachWe estimated recurring dFC clusters from rs-fMRI data and quantified the dwell-time (total duration spent in specific connectivity states) for three cohorts: not-at-risk, A+P-, and A+P+. To evaluate the utility of these temporal features, group differences in dwell-time profiles were assessed, and logistic regression with permutation testing was employed to classify genotypes based on dFC patterns. Main resultsIndividuals in at-risk groups (A+P- and A+P+) exhibited significantly reduced dwell-time in left-hemisphere hubs compared to the not-at-risk group, aligning with known left-hemisphere vulnerability in early AD progression. The logistic regression models achieved above-chance discrimination of genotypes, with permutation tests confirming a significant trend when distinguishing not-at-risk individuals from the combined at-risk cohorts. SignificanceThese findings suggest that the temporal dFC features are sensitive to subtle functional brain alterations linked to AD genetic risk before clinical symptoms appear. Dwell-time features represent a promising physiological marker for early risk stratification and warrant further validation in larger longitudinal datasets. Our code is available at https://github.com/Shyamal-Dharia/APOE-PICALM-dFC-dwell-time.git.

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Dharia, S. Y., Valderrama, C. E., Liu, Q., Smith, S. D.. 2025-12-18. Genetic Interaction of APOE-E-4 and PICALM rs3851179 is Associated With Dynamic Functional Connectivity in Healthy Middle-Aged Adults at Risk for Alzheimer's Disease. https://doi.org/10.64898/2025.12.16.693545

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