In a large South Korean cohort of predominantly cognitively impaired participants, we tested sex differences in WMH, in associations of known risk factors to WMH, and in associations of WMH to longitudinal clinical outcomes. Our study has three main findings. First, females appear to be protected from white matter lesions at middle age but are observed to be more vulnerable at older age compared to males. Second, diabetes status was associated with greater WMH burden in females but not males. Finally, WMHV was associated with worse clinical dementia outcomes longitudinally in females only.
A significant number of studies in the last two decades have observed elder, predominantly postmenopausal females to have a higher prevalence for cerebrovascular burden and disease compared to males4–10, 31. There is limited understanding of the underlying mechanisms through which these sex differences arise, but the different trajectories of endogenous sex hormones has been proposed to play a role. In particular, during the premenopause, endogenous estrogen is thought to be protective for neuronal and cerebrovascular health32, 33. Recently, the Rhineland study reported that postmenopausal females had more WMH compared with premenopausal females and men of the same age range10. Moreover, a recent UK-Biobank study observed that females with a longer reproductive lifespan had significantly smaller WMH burden in late life independent of the history of oral contraceptive use or hormone replacement therapy34. Taken together, our findings contribute to the growing body of literature which displays an increased risk for CSVD in late life for postmenopausal females compared to males of the same age.
Diabetes status and its severity are risk factors for CSVD. Chronic hyperglycemia stimulates the overproduction of mitochondrial superoxide radicals in endothelial cells, resulting in oxidative stress, endothelial dysfunction, and inflammation. These events are associated with the pathogenesis of vascular damage, in both small and large blood vessels35. Numerous cross-sectional and longitudinal studies have displayed an association between diabetes status and HbA1c levels with WMH burden18, 36–39. Large observational studies observe type 2 diabetes confers a greater risk of incident cardiovascular disease in women compared with men40, and evidence also supports a more adverse effect of diabetes on CSVD in females compared to males41. For example, diabetes was reported to confer an increased risk of vascular dementia in females but not males in both a large community-based cohort study as well as a meta-analysis with over 2.3 million individuals42, 43. Some studies have also reported diabetes to be associated with greater WMH or lacune volume in females but not males18–20. Furthermore, animal models have supported the finding that diabetes is associated with worse cerebrovascular burden in females. A recent study observed that when mice are given a high fat diet causing hyperglycemia, white matter damage was only observed in females while neuroinflammatory activation was only observed in males44. Moreover, a study utilizing a genetic mouse model of diabetes reported that females had larger ischemic infarcts compared to males. These infarcts were exacerbated by ovariectomy and ameliorated by E2 treatment, which suggests estrogen directly influences diabetes effect on CSVD45. Collectively, our findings contribute to the idea that diabetes is differentially associated with CSVD burden between sexes. There is still limited understanding of the potential sex-specific mechanisms through which diabetes may incur sex differences in CSVD.
Marked sex differences have been reported for the trajectories of cognitive and clinical decline in dementia. In a pooled analysis of 26,000 participants, females were reported to have greater cognitive reserve but faster cognitive decline than men46. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study displayed that female MCI participants experienced cognitive deterioration faster than males with MCI47, 48. Sex-specific differences in the trajectories of cognitive decline have also been supported by fMRI studies looking at memory network alterations. In particular, in a longitudinal fMRI study, we recently reported that male memory network alterations were more associated with amyloid burden while female’s alterations were more correlated to WMH volume49. Our longitudinal findings on clinical dementia outcomes are similar in that baseline amyloid burden was associated with worse longitudinal CDR-SB scores in both sexes, but only females are associated with worse outcomes due to baseline WMH volume. Our findings also agree with a recent longitudinal study analyzing ADNI participants, where females had worse CDR-SB scores over time compared to males with the same level of WMH burden16. When examining other clinical manifestations of CSVD, some studies reported that females had worse functional outcomes and cognitive decline after stroke50, 51. Combined, our findings suggest that elder females may have less resilience to CSVD burden compared to males.
Our study has limitations. First, we do not have information available regarding participants’ medication use. Uncontrolled hypertension has been reported to be a sex-specific risk factor for WMH10, thus our lack of information on participants’ medication may have contributed to our lack of findings of sex differences in associations of hypertension to WMHV. We do not have information of diabetes medication, but our findings for diabetes status can be supported by our similar observations for HbA1c, which is an indicator for diabetic control. Additionally, we do not have information on menopausal status nor whether participants received hormone therapy. Finally, our hospital-based cohort may have recruitment or survival bias, which has been observed to be associated with higher effect sizes for sex differences in cerebrovascular disease3.
In conclusion, our study provides valuable insights into the complex interplay between sex, modifiable risk factors, and clinical dementia outcomes in the context of CSVD. Elderly females appear to have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Our findings also suggest that females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the risk factors for and cognitive sequelae of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies.