Sex differences in risk factors, burden, and outcomes of cerebrovascular disease in Alzheimer’s disease populations

Background White matter hyperintensity (WMH) accumulation is associated with vascular risk factors such as hypertension, diabetes, smoking, and obesity. Increased WMH burden results in increased cognitive decline and progression to mild cognitive impairment (MCI) and dementia. However, research has been inconsistent when examining whether sex differences influence the relationship between vascular risk factors, WMH accumulation, and cognition. Methods A total of 2119 participants (987 females) with 9847 follow-ups from the Alzheimer’s Disease Neuroimaging Initiative met inclusion criteria for this study. Linear regressions were used to examine the association between vascular risk factors (individually and as a composite score) and WMH burden in males and females. When controlling for vascular risk factors, linear mixed models were also used to investigate whether the relationship between WMHs and longitudinal cognitive scores differed between males and females. Results Males had overall increased occipital ( p <.001), but lower frontal ( p <.001), total ( p =.01), and deep ( p <.001) WMH burden compared to females. For males, history of hypertension was the strongest contributor to WMH burden. On the other hand, the vascular composite score was the strongest factor for WMH in females. Greater increase in WMH accumulation was observed in males with a history of hypertension in the frontal region ( p =.014) and males with high systolic blood pressure in the occipital region ( p =.029) compared to females. With respect to cognition, WMH burden was more strongly associated with longitudinal decreases in global cognition, executive functioning, and functional activities of daily living in females compared to males. Discussion These findings show that controlling hypertension is important to reduce WMH burden in males. Conversely, minimizing WMH burden through vascular risk factors requires controlling many factors for females (e.g., hypertension, diabetes, smoking, alcohol abuse, etc.). The results have implications for therapies and interventions designed to target cerebrovascular pathology and the subsequent cognitive decline. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Dr. Morrison is supported by a postdoctoral fellowship from Canadian Institutes of Health Research, Funding Reference Number: MFE-176608. Dr. Dadar reports receiving research funding from the Healthy Brains for Healthy Lives (HBHL), Alzheimer Society Research Program (ASRP), and Douglas Research Centre (DRC). Dr. Collins reports receiving research funding from Canadian Institutes of Health research, the Canadian National Science and Engineering Research Council, Brain Canada, the Weston Foundation, and the Famille Louise & Andre Charron. ### 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 study used only openly available human data that were originally located from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).