Reviewed by Benedette Cuffari, M.Sc.

Advanced imaging technologies have enabled scientists to better understand the pathophysiology and outcomes of various disease conditions more accurately by tracing the sequence of events in target organs.

A new paper in Alzheimer's & Dementia utilizes imaging findings to elucidate how a common condition like Alzheimer's dementia (AD) can present considerable variations depending on the sex of the individual.

Study: Sex differences in risk factors, burden, and outcomes of cerebrovascular disease in Alzheimer's disease populations. Image Credit: Inside Creative House / Shutterstock.com

Introduction

The presence of white matter hyperintensities (WMH) is a marker of cognitive decline, which leads to mild cognitive impairment (MCI) and, in a proportion of affected individuals, dementia. These pathologies can be visualized on magnetic resonance imaging (MRI) and arise due to cerebral small vessel disease (CSVD).

VMH may be present without cognitive impairment. However, its presence increases the risk of decreased cognition and MCI in older people without other health issues.

The small vessels of the brain undergo damage in various disease states ranging from hypertension and diabetes to obesity, smoking, or drinking. However, these factors operate differently depending on the sex of the individual, such that heavier females with high blood pressure are more likely to have a stroke than males.

This may be attributed to older females often being more hypertensive than males but less likely to have well-controlled blood pressure. Menopause may also trigger potentially detrimental changes in risk in females, such as a sudden rise in blood pressure that remains above desirable levels more often than males of the same age. A history of pre-eclampsia or diabetes in pregnancy could further enhance the risk.

Earlier research has failed to provide conclusive evidence of a difference in WMH burden between the sexes. Nevertheless, some researchers believe that these risk factors do not affect both sexes equally.

The current study reports sex-based differences in observed WMH progression and the differential impact of various risk factors on this progression, as well as how these relate to the cognitive outcome.

What did the study show?

A vascular composite score was developed, which included the presence of self-reported diabetes, alcoholism, smoking, hypertension, and overweight or obesity, in a binary format. The Hachinski score, which is a tool employed to determine the presence of vascular disease and vascular dementia, was also assessed.

The participants were also evaluated by cognitive testing. These test results were correlated with WMH burden on the latest MRI within the last six months.

The mean age of males in the study was 74, whereas the average age of females was about 72. More males than females were hypertensive at 10% and 5%, respectively. Over 50% of males were hypertensive as compared to about 45% of females. Likewise, a greater proportion of males were smokers than women at 40% and less than 30%, respectively, whereas 6% and 2% abused alcohol, respectively.

About 40% of males and 30% of females had a diagnosis of MCI. Moreover, about 55% of females and 40% of males were considered cognitively normal.

WMH burden

The MRI findings showed age-dependent increases in WMH progression in almost all regions of the brain among women. Notable exceptions were observed in the temporal and parietal regions, in which both sexes exhibited equal rates of progression.

The occipital region in males exhibited more WMH. The greatest differences were seen in the deep brain and the occipital region.

In both sexes, WMH progression in all regions except the deep brain was associated with MCI and AD. In women, the occipital region was not affected by WMH.

Men with apolipoprotein E (APOE) risk alleles exhibited greater WMH burden in the occipital and parietal regions. Comparatively, women with this genetic risk factor only exhibited greater WMH burden in the occipital region.

A higher vascular composite score was associated with a greater higher total WMH burden, as well as increased WMH in several regions for men but in all regions for women. Hypertension was associated with more frontal WMH in males than females.

Systolic hypertension was associated with greater occipital WMH in males and deeper WMH in females. Importantly, frontal WMH has been better correlated with vascular disease as compared to parietal WMH with AD.

Among males, the most important risk factor for WMH occurrence and progression was hypertension. Among females, no single vascular risk factor could be identified; however, the vascular composite score correlated with WMH burden.

Overall, however, there are few significant differences in the contribution of the various risk factors examined in this study to the WMH differences between the sexes.”

Cognitive decline

Both sexes were affected to the same extent by WMH. As compared to males, females exhibited a disproportionate loss of global cognition for the WMH level. Females also experienced a greater impact on memory and functional status with the same WMH burden.

This corroborates earlier studies reporting that AD manifests in females at lower levels of brain pathology and deteriorates faster with greater brain atrophy than males. Thus, the female brain may be less resilient when affected by WMH, thereby making it more susceptible to any future strokes or vascular pathology. This increased vulnerability could be the result of decreased estrogen levels that protect cognitive function.

What are the implications?

The study findings indicate that multiple cardiovascular risk factors that could potentially be avoided or mitigated are important in modifying the risk of further cognitive decline and WMH progression. However, the differential contributions of various factors differed between males and females. This should lead to further sex-specific research on cognitive decline.

Future interventions should target hypertension in males but many risk factors in female to help reduce cognitive decline and progression to dementia.”

Journal reference:

• Morrison, C., Dadar, M., & Collins, D. L. (2023). Sex differences in risk factors, burden, and outcomes of cerebrovascular disease in Alzheimer's disease populations. Alzheimer’s & Dementia. doi:10.1002/alz.13452.