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Cardiovascular imaging reveals pathways linking cardiovascular risk factors to brain aging and cognition
Under a Creative Commons license
Open access
Keywords
Brain-heart
Brain age
Cardiovascular risk factors
Cognition
MRI
1. Introduction
Cardiovascular risk (CVR) factors including age, elevated total circulating cholesterol, hypertension, diabetes mellitus, smoking and high body mass index (BMI), are associated with increased risk of brain disorders, including Alzheimer’s disease, other dementias, and age-related cognitive decline (Qiu and Fratiglioni, 2015), suggesting a link between the cardiovascular system and brain health. For example, hypertension and diabetes mellitus are associated with lower total brain volume as well as localized changes in grey mater volume (Lamar et al., 2020). Although cognitive abilities naturally decline with age (Nyberg et al., 2012), exposure to CVR factors might accelerate the pace of aging-related brain changes and cognitive decline (Randhawa and Varghese, 2025, Song et al., 2020).
Biological age can provide a reliable indicator of heart and brain aging (Cole and Franke, 2017). Previous research shows that CVR factors, including anthropometric measurements such as BMI and waist circumference, blood lipids, smoking and blood pressure are associated with the biological age of the brain (Beck et al., 2022). Likewise, the Framingham risk score (FRS) (D’Agostino et al., 2008), an aggregate of CVR factors estimating the risk of future cardiovascular disease, is associated with alterations in brain structure (Marrie et al., 2021, Song et al., 2020) and cognitive performance (Dregan et al., 2013, Kaffashian et al., 2011, Laughlin et al., 2011, Song et al., 2020). Specifically, higher FRS is associated with reduced volumes in the hippocampus, total grey matter, cortical, cerebellar, and subcortical grey matter, and total brain volume, as well as an increase in white matter hyperintensity volume (Song et al., 2020). Moreover, poorer cardiovascular health (Huang et al., 2024) and higher FRS (Wagen et al., 2022) are associated with older brain age. Associations between the biological age of the brain and cardiovascular system have also been reported (Amirmoezzi et al., 2024, Tian et al., 2023) and these studies suggest that advanced cardiovascular aging may contribute to accelerated brain aging. These findings underscore the importance of understanding how age, along with other modifiable CVR factors, influence brain aging, and the pathways through which these effects occur.
The adult brain relies on 15–20% of cardiac output (Xing et al., 2017), making it especially susceptible to disruptions in blood flow. Several factors, such as vascular pathology, cardiac dysfunction, and CVR factors, can impair cerebral circulation (Carmichael, 2014, Moore and Jefferson, 2021, Ovsenik et al., 2021) and impact brain health (van der Velpen et al., 2017). For example, vascular pathology (Moore and Jefferson, 2021) and cardiac dysfunction (Ovsenik et al., 2021) affect hemodynamic status and disrupt cerebral autoregulation, reducing cerebral blood flow and contributing to cognitive decline in the older adults. Similarly, CVR factors such as hypertension, older age, and elevated cholesterol level promote arterial stiffness and damage cerebral vasculature as well as drive the formation of atherosclerotic plaques, leading to restricted blood flow dynamics through stenotic cerebral vessels (Carmichael, 2014). These links motivate our investigation into the specific cardiovascular pathways through which CVR factors may influence brain aging. Given that CVR factors contribute to changes in the structure and function of the cardiovascular system (Petersen et al., 2017, Ren et al., 2015), we hypothesise that these changes reduce cerebral blood flow, which in turn may accelerate brain aging. We also hypothesise that the impact of CVR factors on brain aging is most prominently mediated by specific cardiovascular characteristics, particularly those related to vessels and left ventricular functional capacity, given that cardiac output results from the systolic contraction of the left ventricle and arteries deliver blood to the brain tissue. In contrast, right ventricular measures primarily influence pulmonary circulation and would therefore be less likely to directly mediate the association between CVR factors and brain aging (Bernal-Ramirez et al., 2021, Chandra et al., 2017).
Building on the physiological insights linking cardiovascular health and brain function, emerging imaging research has identified various brain-heart connections (Markousis-Mavrogenis et al., 2022, Zhao et al., 2023). Brain grey matter, white matter and functional connectivity are associated with the morphology and function of the aorta and cardiac chambers (Zhao et al., 2023). Moreover, different heart and brain imaging features are linked to both elevated cardiovascular risk and reduced cognitive function, including myocardial intensity (a proxy for myocardial size), total and grey matter volumes, white matter tract integrity, and white matter hyperintensity volume (Jaggi et al., 2024). These findings suggest that the brain-heart link may underlie the relationship between CVR factors and changes in brain structure and function, as well as cognitive decline. However, previous findings are based on cross-sectional analyses. Longitudinal studies are needed to investigate the potential mediating role of the heart in the relationship between cardiovascular risk and brain health.
Additionally, we explore the potential role of cognitive decline as a terminal point in the pathway linking cardiovascular risk and brain aging. Previous studies establish links between the cardiovascular system and cognition. Better cognitive performance is associated with larger left and right ventricular volumes, higher left and right ventricular stroke volumes, greater left ventricular mass, and greater aortic distensibility (Raisi-Estabragh et al., 2022), whereas cognitive impairment is associated with narrower carotid arteries (Frazier et al., 2014, Yue et al., 2016). More interestingly, a recent study shows that individual variation in grey matter volume can only partially explain the association between myocardial intensity and cognitive function, which suggests that heart structural variations may influence cognitive function through mechanisms independent of brain structural changes (Jaggi et al., 2024). These findings underscore the role of the cardiovascular system in cognitive function, suggesting that cognitive performance is influenced not only by CVR factors but also by cardiac structure and function. Further work is needed to elucidate pathways that may explain the complex interrelationships between CVR factors, heart and brain health and cognition, particularly in aging populations with a high comorbidity of brain and cardiovascular diseases (Eggermont et al., 2012). Exploring the link between cognitive impairment and the structural and functional phenotypes of the cardiovascular system may identify potential targets for early intervention strategies aimed at delaying brain aging and preventing cognitive decline.
In this study, we utilized longitudinal, multiorgan, and multimodal imaging data from the UK Biobank i) to examine the impact of CVR factors on brain aging and cognitive performance; and ii) to assess whether this impact is mediated by the structural integrity and functional capacity of the cardiovascular system (Figure 1). To this end, pathway analysis was conducted to explore the mediating role of different regions of the cardiovascular system, including the cardiac chambers and large arteries. Our work yields new physiological knowledge of how CVR factors lead to brain aging and cognitive decline. We also provide new leads into cardiovascular therapeutic targets for aging-related cognitive decline.
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