Intervention on modifiable lifestyle and physiological factors via variational autoencoder reveals changes in functional connectivity-mediated risk for Alzheimer’s disease
- 1Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States
- 2Department of Biomedical Engineering, Tulane University, New Orleans, LA, United States
Abstract
Alzheimer’s disease (AD) remains without effective treatment, largely due to the fact that clinical symptoms emerge only after decades of silent pathological progression. It is urgently needed to identify modifiable risk factors in earlier life stages, when preventive interventions may still be effective. Functional connectivity (FC) has emerged as a promising neuromarker for both neurodegenerative processes and behavioral traits, making it a potential bridge between early-life health profiles and late-life AD risk. In this work, we introduce a novel integrative framework, called InterventionVAE, that models how early-life lifestyle and physiological factors influence AD risk through their impact on brain FC. Our approach combines a modified variational autoencoder (VAE) that simulates FC changes under interventions with a predictive model that estimates AD risk based on FC patterns. This design enables training of the generative and predictive components under different datasets and populations, with FC acting as the bridge between early-life modifiable factors and late-life disease risk. Applying InterventionVAE to data from the Human Connectome Project (HCP), UK Biobank (UKB), and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we validate its ability to capture known risk factors, such as age and polygenic risk score, on FC-mediated AD risk. We also identify earlier-life modifiable factors including tobacco use, sleep quality, physical activity, and weight/BMI that significantly influence AD risk. Notably, we observe a U-shaped relationship between blood pressure and AD risk, and highlight the brain visual and somatomotor networks as key mediators of risk through FC. Our approach provides a powerful tool for investigating the effect pathways linking early-life interventions to neurodegenerative outcomes, with broad applicability to other brain-related disorders.
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BibTeX
@article{orlichenko2026intervention,
title = {{Intervention on modifiable lifestyle and physiological factors via variational autoencoder reveals changes in functional connectivity-mediated risk for Alzheimer’s disease}},
author = {Anton Orlichenko and Shengxian Ding and Emily Johns and Zhiling Gu and Xinyuan Tian and Xiaoxuan Li and Yize Zhao},
journal = {Imaging Neuroscience},
year = {2026},
month = oct,
doi = {10.1162/imag.a.1408},
url = {https://doi.org/10.1162/imag.a.1408},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Intervention on modifiable lifestyle and physiological factors via variational autoencoder reveals changes in functional connectivity-mediated risk for Alzheimer’s disease
AU - Anton Orlichenko
AU - Shengxian Ding
AU - Emily Johns
AU - Zhiling Gu
AU - Xinyuan Tian
AU - Xiaoxuan Li
AU - Yize Zhao
PY - 2026
DA - 2026/10/22
JO - Imaging Neuroscience
DO - 10.1162/imag.a.1408
UR - https://doi.org/10.1162/imag.a.1408
AB - Alzheimer’s disease (AD) remains without effective treatment, largely due to the fact that clinical symptoms emerge only after decades of silent pathological progression. It is urgently needed to identify modifiable risk factors in earlier life stages, when preventive interventions may still be effective. Functional connectivity (FC) has emerged as a promising neuromarker for both neurodegenerative processes and behavioral traits, making it a potential bridge between early-life health profiles and late-life AD risk. In this work, we introduce a novel integrative framework, called InterventionVAE, that models how early-life lifestyle and physiological factors influence AD risk through their impact on brain FC. Our approach combines a modified variational autoencoder (VAE) that simulates FC changes under interventions with a predictive model that estimates AD risk based on FC patterns. This design enables training of the generative and predictive components under different datasets and populations, with FC acting as the bridge between early-life modifiable factors and late-life disease risk. Applying InterventionVAE to data from the Human Connectome Project (HCP), UK Biobank (UKB), and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we validate its ability to capture known risk factors, such as age and polygenic risk score, on FC-mediated AD risk. We also identify earlier-life modifiable factors including tobacco use, sleep quality, physical activity, and weight/BMI that significantly influence AD risk. Notably, we observe a U-shaped relationship between blood pressure and AD risk, and highlight the brain visual and somatomotor networks as key mediators of risk through FC. Our approach provides a powerful tool for investigating the effect pathways linking early-life interventions to neurodegenerative outcomes, with broad applicability to other brain-related disorders.
SN - 2837-6056
ER -