New clues on sex-specific cerebrovascular aging

Neurodegenerative diseases, including dementias, are a major cause of morbidity and mortality in the United States, especially in the growing aging population (1). Dementia is an overall term for a group of symptoms encompassing impairments in memory, language, concentration, etc. Several conditions fit into the overall grouping of dementia, but Alzheimer’s disease is one of the most common causes of dementia, with an estimated 7.2 million Americans over the age of 65 living with Alzheimer’s disease in 2025 (1). While this disease is extremely prevalent and research efforts have long been aimed at understanding this pathology, many mysteries remain about mechanisms of disease development and progression.

Understanding of the typical presentation of Alzheimer’s disease has greatly improved since its initial documentation in 1907. Alzheimer’s disease is characterized by the accumulation and deposition of amyloid beta (Aβ) peptides outside of neurons and twisted strands of the protein tau inside of neurons (now called ‘neurofibrillary tangles’) (1). Additional features of Alzheimer’s disease can include neuronal cell death, inflammation, and white matter lesions, which leads to atrophy of brain tissue (1). Three of the most notable identified risk factors for Alzheimer’s disease include advancing age, apolipoprotein E genotype (APOE), and female sex, where older individuals, individuals with the APOE ε4 genotype, and women all demonstrate greater prevalence of Alzheimer’s disease (2). These three factors have influenced how the field is moving forward in investigating the disease.

Research has also shown that there are vascular contributions to cognitive impairment and dementias. Dysregulation of cerebral vascular function is an early sign of neurodegenerative disease, where cerebrovascular dysfunction can precede classical signs of disease, such as Aβ deposition, brain atrophy, and white matter lesions (3). This has implicated cerebrovascular function as a candidate for further investigation in the initial development of neurodegenerative diseases.

Vascular Contributions to Cerebral Outcomes

Impaired cerebral blood flow is associated with faster cognitive decline in normal aging adults and adults with previously known cognitive impairments (4). More specifically, cerebral small vessel disease (SVD) is a major vascular driver of lesions in the white matter of the brain, also called white matter hyperintensities (WMH), and WMH are linked with cognitive impairment (5). Cerebral SVD can be caused by damage to smaller resistance arteries and cerebral microvessels via the transmission of high pulsatile wave forms from the peripheral circulation (6). Therefore, new research has started to study how cerebral pulsatility might contribute to brain outcomes.

The primary function of the large peripheral arteries, especially the aorta, is to dampen pulse pressure (i.e., the difference between the systolic and diastolic blood pressure). This creates more uniform blood flow and tissue perfusion throughout the cardiac cycle and lowers the pulsatility of blood flow as it enters end organs, such as the brain, through vulnerable microvessels. It is now well-documented that there are sex differences in how the large peripheral arteries become stiffer with aging, with men developing arterial stiffness about a decade earlier in life relative to age-matched women (7). However, as women become menopausal (i.e., average age ~55 years old), arterial stiffness increases substantially, both increasing at a steeper rate and to an overall greater value in women compared with men as they reach advanced age (7, 8). As the large peripheral arteries become stiffer, greater pulse pressure is then transmitted into the smaller vessels and can cause small vessel and end organ damage (6). Together, this indicates that blood flow pulsatility in the cerebral circulation may be a potential mechanism driving SVD and, thus, aging-associated cognitive impairments and dementias, especially in aging women.

New Clues on Sex-Specific Mechanisms of Vascular Contributions to Cerebral Outcomes

In this issue of the American Journal of Physiology — Heart and Circulatory Physiology, Moir et al. share new findings of sex- and age-specific relationships between cerebral artery pulsatility and WMH (9). In a cohort of 403 cognitively unimpaired men and women between the ages of 45 and 91 years, an index of cerebral pulsatility in multiple cerebral arteries was positively associated with WMH. The authors planned intentional subgroup analyses in this cohort to assess age-dependent, sex-dependent, and interactive effects on the relationship between outcomes. There was a positive relationship between cerebral pulsatility and WMH in the anterior circulation (i.e., internal carotid and middle cerebral arteries) in middle-aged women, but this association was not present in men until older age, suggesting that women may be more vulnerable to cerebrovascular outcomes earlier in life than men. Further, there was a positive association between cerebral pulsatility and WMH in arteries in the posterior circulation (i.e., basilar artery and vertebral arteries) in older-aged women only, indicating a unique, female-specific mechanism of cerebrovascular outcomes.

The authors performed statistical analyses to try to understand how additional variables may be influencing the relationship between cerebral pulsatility and WMH in this cohort. First, mean arterial pressure (MAP) was a significant predictor of WMH in women only, which aligns with previous literature suggesting that blood pressure has a stronger effect on white matter outcomes in females than males (9). Second, there were female-specific confounders of the relationship between cerebral pulsatility in the vertebral artery and WMH, such that this association became statistically significant when HDL cholesterol, LDL cholesterol, and high sensitivity C-reactive protein (hs-CRP, an inflammatory marker) were included as covariates in univariate analyses, and this relationship was no longer statistically significant when MAP, hypertension status, or diabetes status were included as covariates in univariate analyses (9). These findings suggest that several risk factors may have sex-specific effects on cerebrovascular outcomes, but much remains unclear about how specific risk factors correlate with cerebrovascular pulsatility and disease outcomes in age- and sex-specific manners. Future research might consider further investigation into how these variables contribute to the pathogenesis of cognitive impairments and neurodegenerative diseases.

This study also intentionally assessed sex-dependent effects, which is warranted based on the disproportionately high number of women affected by Alzheimer’s disease, as well as worsened outcomes and faster progression observed in women (1, 2). However, this study cohort was not stratified by menopausal status. There has been a long-observed association between menopause and women’s Alzheimer’s disease risk (2). Further, we know that peripheral arterial stiffness increases across the menopausal transition as well (8), supporting that there may be transmission of greater pulsatility from the peripheral circulation into the cerebral circulation with menopause in aging women. Therefore, future studies should focus on the influence of menopause in the relationship between cerebrovascular outcomes, such as cerebral pulsatility, studied here, and WMH or cognitive decline.

This study used 4D flow magnetic resonance imaging (MRI) to assess cerebral pulsatility, which is more sensitive than traditional methods at recognizing aging-associated changes (10). Another strength of using 4D flow MRI in this study is the capability it provides to assess outcomes in multiple vessels, as opposed to previous methods. Through this methodology, this study identifies two results that remain unexplained: correlations between cerebral pulsatility and WMH that are 1) brain region specific and 2) unilateral at times. These findings suggest that there may be regional differences in vessel properties (e.g., structure, hemodynamics, distribution of cerebral blood flow) contributing to cognitive impairments or neurodegenerative disease. Further, regional and unilateral differences raise the question of how this might differentially affect the areas of the brain supplied by the affected vessels between hemispheres and how that might influence specific outcomes of disease.

In summary, this study identifies that cerebral pulsatility in multiple cerebral arteries is associated with greater WMH within the aging brain (Figure 1). These observations are particularly evident in women, with associations in the anterior cerebral circulation evident earlier in life in women than men and in the posterior cerebral circulation exclusively in older aged women. Overall, this study has provided clues into how future investigations may aim to address biological sex- and aging-dependent cerebrovascular outcomes and how this helps our understanding of the contribution of vascular dynamics to the development and/or progression of cognitive impairment and neurodegenerative diseases.

Figure 1.

An index of pulsatility in cerebral arteries correlates with the presence of white matter hyperintensities within the brain in a sex- and age-dependent manner, highlighting a specific vulnerability of heightened pulsatility in aging women. Menopausal status may be a crucial next step for understanding female-specific cerebrovascular contributions to cognitive impairments and dementia. Risk factors, such as blood pressure, diabetes, cholesterol, and inflammatory markers (e.g., high sensitivity C-reactive protein, hs-CRP), also may display age- and sex-dependent influence on the development of disease, which warrants further investigation.