Vascular risk factors modulate gender-specific aging of brain white matter structural network

Vascular risk factors (VRFs) are known to increase risk for cerebrovascular disease and dementia, such as Alzheimer’s disease that is described as a dysconnectivity syndrome. The gender-related evidence on associations between VRFs and white matter (WM) structural network in large community-dwelling populations across middle and older age will contribute to understanding the biological underpinnings of sex and gender considerations in dementia. Based on 17,954 participants from the UK Biobank, we present the relationship between VRFs and WM network architecture (measured with network integration and segregation) in different gender groups. First, females exhibit lower network architecture and experience an accelerated decline earlier than males. Second, network integration is more sensitive to VRFs than segregation, with diabetes, hypertension, and excessive alcohol consumption having the greatest impact. Third, we found greater susceptibility of network architecture to VRFs in males, as well as female-preferred effects on regional integration of obesity, particularly on the subcortical structure and occipital lobe. Finally, higher combined risk was associated with more disrupted network architecture particularly on temporal and frontal lobe, as well as lower processing speed and working memory in both genders. Our findings provide new insights into understanding the relationship between VRFs and WM network architecture, guiding interventions to promote successfully cognitive aging and highlighting the importance of considering gender-specific effects in future research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the STI2030-Major Projects (2022ZD0213300), National Natural Science Foundation of China (32271145, 81871425), Fundamental Research Funds for the Central Universities (2017XTCX04), Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning (CNLZD2101, CNLYB2001). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The North West Multi-centre Research Ethics Committee (MREC) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request. All data produced are available online at