Cardiovascular contributions to dementia: Examining sex differences and female-specific factors.

The American College of Cardiology/American Heart Association defines hypertension as a systolic blood pressure ≥130 mmHg and/or a diastolic blood pressure ≥80 mmHg, 32 though specific cutoffs may vary between different clinical practice guidelines. While men typically have higher blood pressure levels and experience steeper blood pressure increases earlier in life, this pattern reverses around age 60 – coinciding with the post‐menopausal period in women. After this time, women experience sharper increases in blood pressure compared to men. 33 , 34 , 35 Increased risk for hypertension is especially pronounced among women who undergo menopause at earlier ages, experience vasomotor symptoms of menopause (e.g., hot flashes, night sweats), and/or have additional cardiovascular risk factors. 20 Notably, women face a higher risk of CVD than men at lower blood pressure levels, which is likely related to sex differences in vascular structure and function. 36 , 37 High blood pressure (especially systolic) is a well‐established contributor to cognitive decline and dementia in mixed‐sex studies. 38 , 39 Emerging evidence suggests that hypertension, particularly during midlife, increases the risk of late‐life dementia more strongly in women than in men. 26 , 40 , 41 Several mechanisms may underlie this sex‐specific susceptibility. In women, hypertension has been associated with more rapid gray matter atrophy, a higher burden of white matter hyperintensities, and more severe damage to white matter microstructure compared to men. 26 , 42 , 43 , 44 , 45 One study reported that hypertension was more strongly related to greater white matter hyperintensity burden in frontal and occipital regions in men than in women, whereas women with hypertension showed a greater burden of deep white matter hyperintensities than men. 46 Additionally, although low blood pressure is not conventionally considered a cardiovascular risk factor, late‐life decreases in blood pressure (especially systolic) have been associated with cerebrovascular pathology, AD pathology, and mortality. 47 , 48 , 49 Interestingly, recent findings show that declining systolic blood pressure in late life is associated with cognitive decline in women but not in men. 50 Dyslipidemia is characterized by elevated levels of total cholesterol, low‐density lipoprotein (LDL) cholesterol, and triglycerides, along with reduced levels of high‐density lipoprotein (HDL) cholesterol. 51 While premenopausal women typically have more favorable lipid profiles compared to age‐matched men, LDL and total cholesterol levels increase considerably in women later in life, eventually surpassing those observed in men. 52 , 53 , 54 The menopause transition has been consistently associated with increases in LDL cholesterol and apolipoprotein B, 55 a structural protein found in atherogenic lipoproteins that reflects the number of cholesterol‐carrying particles. There is mixed evidence regarding whether dyslipidemia affects CVD risk differently in men and women. 56 , 57 , 58 , 59 Compared to men, women are less likely to be prescribed high‐intensity statins and to reach recommended treatment targets. 60 , 61 , 62 Meta‐analyses and large‐scale mixed‐sex studies consistently demonstrate a link between elevated LDL cholesterol in midlife and increased risk of late‐life dementia. 63 , 64 , 65 However, research examining sex differences remains limited. One study in a Chinese population found that higher LDL cholesterol was associated with faster cognitive decline and a greater risk of dementia in women, but not men. 66 In terms of HDL, mixed‐sex studies generally do not show associations between lower HDL cholesterol and greater dementia risk. 63 , 64 , 65 However, two studies reported such an association in men, but not in women. 66 , 67 Conversely, another study showed that a higher HDL/apolipoprotein A ratio (i.e., a marker of the functionality of HDL in removing cholesterol from the arteries, with higher ratios associated with greater CVD risk 68 ) was linked to greater dementia risk in men, but not women. 69 In terms of brain outcomes, one study found that lower HDL cholesterol was associated with faster brain atrophy in men but not women, 45 while another reported that lower HDL cholesterol was linked to a higher burden of white matter lesions in women but not men. 70 Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by elevated blood glucose levels resulting from insulin resistance. 71 Although T2D is more prevalent in men than women, 72 it is more strongly associated with CVD and all‐cause mortality in women than men. 73 , 74 , 75 Moreover, some research suggests that compared to men, women show higher rates of adverse drug reactions to common glucose‐lowering medications 76 and experience more psychological distress related to T2D and its management. 77 Several large studies report that women with T2D are at higher risk of cognitive decline and dementia compared to men, 78 , 79 , 80 a sex difference that may extend to prediabetes. 81 In a study of 893 older adults from a memory clinic, diabetes (with no differentiation of T1D vs T2D) was associated with brain atrophy and lacunar infarcts in women, but not in men. 82 Similarly, another study of comparable size reported an association between T2D and white matter hyperintensities in women, but not in men. 83 Together, these studies suggest that T2D may have a more pronounced impact on brain and cognitive health in women than in men. The prevalence of obesity has tripled over the past four decades, 84 with nearly a third of the world's population classified as overweight or obese. 85 Obesity strongly increases CVD risk. 86 In women, visceral fat accumulation accelerates after menopause, and this type of fat deposition is more strongly associated with CVD than subcutaneous fat. 87 Obesity is commonly measured using body mass index (BMI), waist circumference, or waist‐to‐hip ratio. Of these measures, the latter two more accurately reflect visceral adipose tissue and have well‐established sex‐specific and ethnic thresholds. 1 , 88 , 89 Findings are mixed regarding whether obesity has sex‐specific effects on CVD, with some studies showing greater risk for women 90 , 91 , 92 and others showing no sex difference. 93 One issue is that measures of obesity often underestimate risk in women. For example, an analysis of data from the Framingham Heart Study found that BMI and waist circumference significantly underpredicted cardiometabolic risk and CVD events relative to computed tomography measures of visceral adipose tissue in women, while the three measures were similarly accurate in men. 94 Similarly, a study from Taiwan reported that optimal BMI and waist circumference cutoffs for detecting subclinical cardiac dysfunction in women were substantially lower than those recommended by current clinical guidelines, as obesity was more strongly predictive of adverse cardiac changes in women than in men. 95 Mixed‐sex studies consistently demonstrate that midlife obesity increases the risk of late‐life dementia. 87 , 96 , 97 However, this relationship appears to reverse in older age, such that late‐life obesity is associated with a reduced risk of dementia. 96 , 98 , 99 This phenomenon, often referred to as the obesity paradox, 100 may be partly explained by the fact that weight loss can be an early consequence of neurodegenerative pathology. 99 Since weight loss often precedes a dementia diagnosis by up to 10 years, the seemingly protective effect of higher BMI in late life may reflect reverse causality. 96 , 98 , 99 Research examining sex differences in the relationship between obesity and dementia has yielded discrepant findings. Several studies have reported that midlife obesity is more strongly associated with risk of cognitive decline and dementia in women than in men. 101 , 102 , 103 By contrast, in the Baltimore Longitudinal Study of Aging, a lower midlife BMI was related to a higher risk of AD in men, whereas central obesity, measured by waist‐to‐hip ratio, was associated with an increased risk of AD in women. 104 A cross‐sectional analysis of amyloid beta (Aβ)‐positive participants in the A4 study (with a mean of age of 72) found that obesity (as measured via BMI) was associated with worse cognition in men, whereas obesity was linked to better cognition and lower Aβ and tau burdens in women. 105 Another study found that lower self‐reported BMI in midlife was associated with greater Aβ burden and reduced cortical thinning in men, but not in women. 106 These inconsistent findings may relate to interactions between sex, obesity, and endocrine factors. In postmenopausal women, central adipose tissue serves as a primary source of estrogens, 107 which may exert neuroprotective effects. Supporting this possibility, a large‐scale neuroimaging study showed that abdominal adiposity was associated with attenuated brain aging in women with shorter lifetime exposure to endogenous estrogens. 108 Tobacco smoking accounts for one in four CVD‐related deaths in the United States. 109 While smoking prevalence is lower among adult women than adult men, 110 women tend to experience higher levels of cigarette dependence 111 and face greater challenges quitting. 112 This may be partly due to the reduced efficacy of smoking cessation medications in women. 113 Meta‐analyses report that women have a higher risk of CVD from smoking compared to men. 114 , 115 In addition, smoking in women is associated with an earlier onset of menopause, 116 which in turn is associated with increased risk of CVD. 117 Research examining sex‐specific effects of smoking on dementia risk remains limited. A large cross‐sectional study observed that current smoking was more strongly associated with worse verbal recall in women than in men. 118 Conversely, a longitudinal study reported that current smoking was more strongly linked to declines in global cognition and executive function in men than in women. 119 Other studies have found no sex‐specific effects of smoking on cognition or dementia risk. 40 , 120 , 121 Regarding brain outcomes, one study reported that smoking was associated with reduced gray matter volume in men, reduced white matter volume in women, and greater longitudinal hippocampal atrophy in women compared to men. 122 A small study of adults aged 60 to 64 found that current smoking was associated with greater white matter hyperintensity burden in women but not men. 123 These conflicting findings underscore the need for further research to better understand how smoking may differentially affect  cognition and brain health in women and men. Physical inactivity is a well‐established risk factor for CVD. 124 , 125  Research shows that a higher proportion of women are physically inactive compared to men, 126 a disparity that becomes more pronounced with age. 127 Several factors contribute to lower physical activity levels among women and girls, including limited social support for physical activity, 128 reduced investment in female sports, 129 and time limitations due to family and household responsibilities. 130 Experimental studies show blunted cardiovascular and metabolic adaptations to exercise in women compared to men, 131 , 132 especially after menopause. 133 Interestingly, and somewhat paradoxically, epidemiological evidence indicates that physical activity is associated with a greater reduction in CVD risk and mortality in women than in men. 134 , 135 , 136 , 137 Meta‐analytic evidence from randomized trials suggests that women derive greater cognitive benefits from physical activity than men. 138 , 139 However, findings are mixed for brain outcomes. Some observational studies report that physical activity is more strongly associated with favorable structural brain outcomes in men than in women, 140 , 141 while others report the opposite pattern. 142 Studies investigating other brain‐related measures have also reported inconsistent findings. For example, one study reported that physical activity was more strongly related to greater white matter integrity in men than in women. 141 Another study reported that physical activity was linked to increased blood flow in medial parietal regions in women, but lower Aβ burden in the same regions in men. 143 These discrepancies may, in part, reflect differences in how physical activity was defined and measured across studies (e.g., self‐reported vs objective). Given that the accuracy of self‐reported physical activity may differ by sex, 144 intervention trials will be critical to clarify sex differences in the effects of physical activity on brain health.

This review synthesized existing, publicly available information, so consent was not necessary.

The preceding review highlights that conventional CVD risk factors – such as hypertension, dyslipidemia, diabetes, obesity, smoking, and physical inactivity – affect men and women differently, often conferring greater risk for both CVD and dementia in older women than in older men. Female‐specific factors (e.g., menopause, PCOS, adverse pregnancy outcomes) and female‐predominant conditions (e.g., autoimmune disorders, breast cancer) may further exacerbate these risks in women. Accordingly, the methods used to quantify CVD risk in AD/ADRD studies have important implications for the detection and interpretation of sex differences. While the research reviewed above primarily describes the impact of individual CVD risk factors on cognitive and brain outcomes, many studies have assessed the combined impact of multiple CVD risk factors on dementia risk. 287 , 288 , 289 , 290 , 291 This approach may be preferable, as CVD risk factors commonly co‐occur, 292 further increasing the likelihood of CVD events. 293 However, current methods for quantifying multiple co‐occurring risk factors rarely account for sex differences, which may lead to a systematic underestimation of both CVD and dementia risk in women. A common method for estimating aggregate CVD risk is the use of tally scores, which count the number of conventional CVD risk factors present (e.g., hypertension, diabetes, obesity, smoking), typically assigning one point per condition. 46 , 190 , 294 These tally scores are simple to use and can be adjusted based on available data. However, because they use dichotomous (yes/no) categorizations, they lose the granularity that continuous measures provide (e.g., the spectrum and severity of risk). Dichotomous classifications for conventional CVD risk factors typically rely on established diagnostic thresholds, some of which have sex‐specific cutoffs and some of which do not. For example, dyslipidemia 1 and waist–hip ratio 89 have established sex‐specific thresholds, while diabetes 71 and hypertension 32 do not, despite evidence suggesting that the cutoffs for the latter two conditions should differ by sex and/or menopause status. 295 , 296 The failure to consistently implement sex‐specific cutoffs may lead to the underestimation of CVD risk in women, potentially resulting in inaccurate conclusions about sex differences in AD/ADRD outcomes. Tally scores also typically do not include female‐specific risk factors and assume equal weighting of all variables, which may not accurately represent the true contribution of each factor to CVD risk in each sex. Some of these issues may be mitigated by the use of sex‐specific CVD risk algorithms, 293 , 297 , 298 , 299 , 300 such as the Framingham Risk Score, 293 PREVENT 301 (which replaced the ASCVD 302 ), SCORE2, 303 and QRISK3. 304 These risk algorithms incorporate continuous measurements for some variables and adjust the weighting of risk factors based on sex, thereby partially overcoming the limitations of tally‐based approaches. However, even these sex‐specific algorithms have been shown to underpredict CVD risk in women (i.e., Framingham, QRISK). 305 , 306 This underestimation may stem from the fact that most risk algorithms are heavily influenced by age, and men tend to develop CVD at younger ages than women. 307 , 308 Because women generally live longer, and most algorithms estimate 10‐year risk rather than lifetime risk, CVD risk in women may be underestimated. 309 This limitation is especially relevant in AD/ADRD research, which primarily involves older adults. Moreover, most risk algorithms omit female‐specific risk factors (e.g., menopause history, adverse pregnancy outcomes), female‐predominant conditions (e.g., autoimmune diseases), and lifestyle indicators (e.g., physical activity) that may have sex‐specific effects on CVD risk. Emerging evidence demonstrates that incorporating these often‐overlooked variables significantly improves the accuracy of CVD risk estimates, 310 particularly for women who might otherwise be misclassified as low risk by traditional tools. 311 Supporting this approach, a new population‐based CVD risk score, QR4, which includes female‐specific factors, such as preeclampsia and postnatal depression, outperforms ASCVD, QRISK3, and SCORE2 in predicting CVD risk in women. 312 Beyond these algorithms, latent variable modeling offers another approach for estimating aggregate CVD risk. 313 This person‐centered method identifies how risk factors co‐occur within individuals and generates individualized risk profiles. 313 Studies using latent class analyses in large datasets have identified CVD risk profiles and their associations with dementia outcomes. 314 , 315 , 316 Importantly, invariance testing of these latent class structures can reveal how CVD risk factors cluster differently in women and men. For example, one study found that profiles of modifiable dementia risk factors differed by sex and that these sex‐specific risk profiles were differentially associated with brain imaging markers, cognitive performance, and dementia risk. 313 These data‐driven approaches may offer a more precise understanding of how CVD risk affects dementia outcomes in each sex. While the optimal method for operationalizing CVD risk in studies of sex differences depends on the specific research question, researchers should carefully consider how their selected approach influences the interpretation and clinical relevance of their findings. A key consideration when evaluating and synthesizing findings on sex differences as they relate to the impact of CVD risk burden on AD/ADRD outcomes is the distinction between relative versus absolute sex differences. For example, using sex‐specific algorithms or sex‐specific cutoffs allows researchers to evaluate sex‐adjusted relative risks, since the operationalization of CVD risk differs between men and women. By contrast, analyzing individual risk factors as continuous variables with AD/ADRD outcomes enables estimation of absolute differences in risk between the sexes. While this approach allows for a direct comparison, it limits the ability to assess the combined influence of multiple co‐occurring CVD risk factors. Applying uniform cutoffs across sexes (such as in tally scores) also allows for absolute comparisons but, as noted earlier, may underestimate CVD risk in women, potentially leading to inaccurate conclusions about sex disparities in dementia risk. Together, these considerations underscore the importance of using diverse methodological approaches and conducting detailed sex‐specific analyses to accurately characterize the vascular pathways to AD/ADRD in both sexes. Figure  1 illustrates the pathways linking CVD risk factors, CVD, and AD/ADRD, highlighting that sex‐specific factors may influence both the strength and direction of these associations. Pathways between risk factors for cardiovascular disease (CVD), cardiovascular dysfunction/CVD, and Alzheimer's disease and related dementias (AD/ADRD) outcomes. The figure illustrates that sex differences and sex‐specific factors may influence the development of CVD risk factors, the manifestation of CVD, and progression to AD/ADRD, as well as the strength and direction of the associations among these conditions. Arrows represent possible direct and indirect pathways, with female (♀) and male (♂) symbols potential sex differences.

Much work remains to understand how cardiovascular health influences AD/ADRD risk in women and how these pathways may differ from those in men. There is a critical need for more accurate methods to quantify CVD risk burden in both men and women, including the development of sex‐specific diagnostic thresholds for cardiovascular risk factors and conditions. Equally important is the need to address female‐specific and female‐predominant risk factors that are too often overlooked in CVD and AD/ADRD research. At a minimum, researchers should conduct and report statistical analyses to examine potential sex differences in vascular contributions to AD/ADRD. In parallel, efforts must be made to enhance the representation of diverse populations in large studies and to conduct deep‐phenotyping studies focusing on specific groups of interest. Together, these advances will pave the way for personalized prevention and treatment strategies for AD/ADRD. Ultimately, adopting a sex‐informed approach to studying cardiovascular contributions to AD/ADRD is essential for improving brain health outcomes in all individuals.

Cardiovascular and metabolic conditions, such as hypertension, dyslipidemia, diabetes, and obesity, are well‐established risk factors for cardiovascular disease (CVD), including coronary heart disease, atrial fibrillation, and heart failure. 1 CVD is the leading cause of death among women. 2 Importantly, many risk factors for CVD also increase the risk of Alzheimer's disease and related dementias (AD/ADRD). 3 , 4 , 5 , 6 In fact, half of the top 14 modifiable risk factors for dementia (i.e., high cholesterol, physical inactivity, diabetes, smoking, hypertension, obesity, and excessive alcohol consumption) are directly linked to cardiovascular health. 7 This overlap underscores the critical importance of prioritizing cardiovascular health as a key strategy for preventing AD/ADRD. 8 Given that AD/ADRD, CVD, and their shared risk factors all show significant sex differences, 9 , 10 , 11 , 12 adopting sex‐informed approaches is essential for developing effective interventions to address cardiovascular contributions to AD/ADRD in both women and men. In this review, we use the terms “women” and “men” in accordance with the terminology used in most of the original studies we reference. However, these designations were likely based on sex assigned at birth. Sex refers to the biological and physiological characteristics that distinguish females and males, including but not limited to differences in sex chromosomes, gene expression, hormones, anatomy, physiology, and other biological processes. In contrast, gender refers to socially constructed roles, behaviors, expressions, and power dynamics ascribed to diverse gender identities. 13 For simplicity, we use the terms “women” and “men” to describe participants as reported in the original studies, while acknowledging that both sex‐ and gender‐related factors likely contribute to the sex differences we discuss. AD is the leading cause of dementia and disproportionately affects women, who represent nearly two‐thirds of those diagnosed. 9 , 14 Relative to men, women show greater burdens of AD and cerebrovascular pathology 15 , 16 , 17 and faster cognitive decline in the presence of AD pathology. 18 In the context of CVD, women tend to experience cardiovascular events later in life than men, often after menopause, and have a higher risk of complications and worse outcomes than men. 11 , 12 , 19 Furthermore, many cardiovascular and metabolic conditions, such as hypertension, dyslipidemia, and diabetes, increase the risk of CVD more strongly in women than in men. 11 , 12 , 20 This risk is further compounded by female‐specific factors, including menopause and adverse pregnancy outcomes, as well as female‐predominant factors such as a history of breast cancer. 21 , 22 , 23 Despite their relevance, these factors are often overlooked in research on cardiovascular contributions to AD/ADRD, 24 leaving critical gaps in our understanding of their roles in late‐life cognitive decline and dementia risk. Despite the well‐established sex differences in both AD and CVD as well as the recognized role of vascular contributions to AD/ADRD, 25 , 26 , 27 , 28 , 29 , 30 , 31 research examining sex‐specific links between CVD risk factors and AD/ADRD remains limited. This gap underscores the need for sex‐informed research approaches to better understand how cardiovascular health influences AD/ADRD risk, to advance precision strategies for dementia prevention and treatment in all individuals. In this narrative review, we examine sex differences in conventional CVD risk factors (e.g., those recognized by the American College of Cardiology/American Heart Association 1 ) as well as female‐specific and female‐predominant risk factors (Table  1 ). We discuss the impact of these factors on both CVD and AD/ADRD risks, highlighting that many are more strongly linked to dementia in women than in men. We also examine current approaches to quantifying CVD risk in AD/ADRD studies, noting that many methods may underestimate dementia risk in women. We discuss the importance of incorporating sex‐specific considerations in studies of cardiovascular contributions to AD/ADRD. Finally, we make recommendations for future research to advance precision and equity in dementia prevention and treatment. Conventional, female‐specific, and female‐predominant risk factors for cardiovascular disease Abbreviation: CVD, cardiovascular disease. This paper is not intended to serve as a systematic review of all existing evidence on sex differences in cardiovascular contributions to AD/ADRD. Rather, our goal is to highlight the many important ways in which sex differences and sex‐specific factors may influence vascular pathways to dementia and to equip researchers with actionable strategies for identifying and interpreting these effects. To this end, we focus on studies involving human participants and prioritize those with clinically relevant outcomes such as incident CVD, incident dementia, or their upstream markers (e.g., cardiac function, AD pathology, brain structure, cognitive decline), as available and applicable.

The authors declare no conflicts of interest. Author disclosures are available in the supporting information .

The previously outlined research gaps and methodological limitations have substantially hindered our understanding of cardiovascular contributions to AD/ADRD, especially in women. Advancing our knowledge of sex differences in these pathways holds considerable promise for uncovering the mechanisms underlying AD/ADRD and for informing precision strategies to prevent and treat dementia in both sexes. We propose several recommendations to guide future research efforts on sex differences as they relate to cardiovascular contributions to AD/ADRD. Despite substantial evidence that sex‐specific factors influence CVD outcomes, these variables are rarely incorporated into studies examining vascular contributions to AD/ADRD. Only a small fraction of neuroscience studies consider sex differences or report sex‐disaggregated data, 317 and fewer than 0.5% of published neuroimaging studies address factors related to women's health. 318 To close these critical gaps, brain aging studies should systematically collect data on sex‐specific factors. This includes detailed histories of menstruation and menopause, past and current use of hormonal contraceptives and menopausal hormone therapy, gynecological procedures, reproductive and gestational history, depression, as well as conditions such as autoimmune disorders, PCOS, and endometriosis. Figure  2 illustrates how these factors influence women's cardiovascular and brain health across the lifespan, highlighting the importance of a sex‐informed, life‐course approach. Table  2 outlines key variables that should be incorporated into future studies to support this approach. While a detailed review of male‐specific variables that influence CVD and AD/ADRD outcomes is beyond the scope of this paper, we provide recommendations applicable to both sexes. Key factors influencing cardiovascular and brain health across the female lifespan. This framework underscores the importance of sex‐informed study designs, data collection, and a life‐course approach to research on brain aging in women. It highlights the critical windows along the aging trajectory during which risk factors for Alzheimer's disease and related dementias may be most effectively identified, prevented, or modified to support optimal cognitive and brain health. PCOS, polycystic ovary syndrome; MHT, menopausal hormone therapy. Conditions and history to inquire about in studies examining cardiovascular disease and Alzheimer's disease and related dementias in women and men Despite mandates from major funding agencies in the United States, Canada, and the European Union to treat sex as a biological variable, 319 most studies do not adequately assess sex effects. 317 , 320 To improve rigor in the field, we strongly encourage researchers to explicitly test for interactions between sex and primary variables of interest and to report results disaggregated by sex. Importantly, non‐significant interaction effects should be interpreted cautiously, as they may reflect insufficient statistical power or underlying sex‐specific mechanisms that do not translate into observable differences in outcomes. 317 , 321 To improve transparency and reduce bias in the literature, 322 we recommend reporting all findings, including non‐significant results and their corresponding effect sizes. 323 Sex and gender both influence CVD outcomes and should be carefully considered when formulating research questions and interpreting findings related to vascular contributions to AD/ADRD. However, our understanding of how gender identity and norms affect brain health remains limited. This is due in part to the lack of standardized methods for measuring gender in dementia research. 322 Gender, as both an identity and a social role, interacts with contextual factors such as education, occupation, socioeconomic status, healthcare access, and experiences of gender‐based discrimination and inequities. These interactions can shape both CVD and dementia outcomes. For example, structural sexism has been shown to accelerate memory decline in women living in the United States, an effect that was most pronounced among Black (vs White) women. 324 Researchers are encouraged to integrate historical, sociocultural, and economic frameworks when interpreting sex and gender differences in both CVD and AD/ADRD risk, as these broader contexts can shape both exposure to risk factors and downstream health outcomes. 322 Addressing the underrepresentation of sexual and gender minority groups in aging research is also essential. Evidence suggests that individuals with minoritized gender identities face a greater burden of chronic health conditions, including CVD, 325 and are at increased risk of AD/ADRD. 326 Furthermore, gender may interact with biological factors to modify health outcomes, as demonstrated by the effects of cross‐sex hormone use in transgender adults. 327 Prioritizing inclusive and representative research will not only enhance our understanding of the roles of gender in AD/ADRD but also contribute to the development of more equitable and effective prevention and treatment strategies. 328 , 329 Many existing studies rely on cohorts that lack diversity in gender identity, race/ethnicity, socioeconomic background, and other key demographic factors. Expanding diverse representation in research cohorts is crucial to ensure that findings are equitable and generalizable. This requires intentional efforts to recruit individuals from historically underrepresented and underserved populations, including sexual and gender minorities, to better reflect the diversity of those affected by CVD and AD/ADRD.

Pregnancy induces substantial physiological changes, including endothelial, cardiac, metabolic, immune, hormonal, and other adaptations to support fetal growth and development. 145 , 146 , 147 These changes can trigger the onset of new cardiovascular dysfunction and/or unmask pre‐existing cardiovascular vulnerabilities, potentially leading to complications such as gestational hypertensive disorders, gestational diabetes, and cardiac diseases of pregnancy (e.g., peripartum cardiomyopathy, spontaneous coronary artery dissection, arrythmias, and myocardial infarction, among others). 145 , 148 In developed countries, up to a third of women who have given birth have experienced one or more of these adverse pregnancy outcomes, 149 which are associated with an increased risk of CVD later in life. 147 , 150 , 151 , 152 , 153 Additionally, women with a history of stillbirth, small‐for‐gestational‐age infants, placental abruption, infertility, or in vitro fertilization also have a higher risk of future CVD. 22 , 154 , 155 , 156 Very limited research has investigated the associations between adverse pregnancy outcomes and dementia risk. A Danish nationwide cohort study reported that women with a history of preeclampsia had an increased risk of dementia, even after adjusting for conventional vascular risk factors. 157 Similar findings were reported in a recent meta‐analysis, which observed that pregnancy‐related hypertensive disorders (e.g., gestational hypertension, preeclampsia/eclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were associated with an increased risk of all‐cause dementia, including AD and vascular dementia. 30 Consistent with these findings, studies comparing women with hypertensive pregnancy disorders to those with normotensive pregnancies showed that the former group of women had smaller brain volumes and greater burdens of white matter hyperintensities later in life. 158 , 159 , 160 Menopause, clinically defined as the cessation of menstrual periods for 12 consecutive months, occurs at an average age of 51 years. 161 Early menopause refers to menopause between the ages of 40 and 45, while premature menopause occurs before the age of 40 and can result from primary ovarian insufficiency. 162 In addition to occurring spontaneously, menopause may also be induced surgically via bilateral oophorectomy or as a consequence of chemotherapy or radiation treatment. 55 Spontaneous menopause is characterized by a significant decline in estradiol due to the depletion of ovarian follicles. 163 Estradiol, the most abundant estrogen in premenopausal women, plays a crucial role in cardiovascular and neurological health. 164 , 165 , 166 , 167 It helps maintain the vasculature by promoting blood vessel elasticity and enhancing endothelial function. 165 , 167 In the brain, estradiol supports synaptogenesis, facilitates neural repair, and exerts anti‐inflammatory and antioxidant effects. 164 , 166 Substantial evidence indicates that menopause increases the risk and accelerates the progression of CVD, with worse outcomes observed in women who experience premature, early, or surgical menopause. 55 , 117 , 168 , 169 , 170 , 171 In recognition of this, the American Heart Association now lists menopause history as a female‐specific CVD risk factor. 172 Additionally, moderate‐to‐severe vasomotor symptoms of menopause are linked to CVD risk factors and CVD events. 173 Menopause is also associated with changes in the brain. Postmenopausal women show worse ADRD outcomes compared to age‐matched premenopausal women and age‐matched men. Specifically, they show reduced gray matter in AD‐vulnerable regions, increased Aβ and tau burdens, and decreased brain glucose hypometabolism. 174 , 175 , 176 , 177 In addition, earlier (vs later) menopause (including surgical menopause) is associated with poorer performance on cognitive tests at midlife, 178 , 179 , 180 , 181 an increased risk of late‐life cognitive decline and dementia, 182 , 183 , 184 more pronounced gray matter atrophy in medial temporal regions, 185 lower white matter integrity, 185 , 186 and a greater burden of AD pathology. 184 , 187 Vasomotor symptoms of menopause have also been linked to white matter hyperintensities as well as plasma measures of Aβ. 188 , 189 Additionally, earlier menopause combined with CVD risk factors may have a synergistic effect that accelerates cognitive decline. 190 One potential mechanism connecting menopause, vascular health, and neurodegenerative outcomes involves the glymphatic system – a waste clearance pathway in the brain responsible for removing metabolic byproducts, including Aβ. 191 Menopause accelerates vascular aging including arterial stiffening, 192 and women with earlier‐onset menopause have worse endothelial function compared to their later‐onset counterparts. 193 These menopause‐related vascular changes may negatively affect the glymphatic system. Supporting this, a recent neuroimaging study found that women experienced greater age‐related declines in clearing cerebrospinal fluid than men, an effect primarily driven by postmenopausal women. 194 MHT is currently approved for four main indications: the treatment of vasomotor symptoms, prevention of bone loss, management of premature hypoestrogenism (e.g., following oophorectomy), and treatment of moderate to severe vulvovaginal symptoms. 162 In the late 20th century, MHT was widely regarded as a promising strategy to reduce the risk of CVD, dementia, and other chronic conditions. 2 , 195 However, findings from the Women's Health Initiative (WHI) randomized trial and its substudies challenged this view, reporting increased risks of breast cancer, cardiovascular events, stroke, and dementia among MHT users relative to placebo. 196 These findings led to a sharp decline in MHT use. 197 Subsequent analyses revealed that the effects of MHT on CVD and dementia depend on several key factors, including baseline health status, the timing of MHT initiation relative to menopause, the route of administration, and the MHT formulation. 55 , 170 , 198 Notably, many participants in the WHI initiated MHT more than a decade after menopause and had pre‐existing CVD risk factors, which are known to increase the risks of adverse MHT outcomes. 170 It is now understood that initiating MHT closer to the onset of menopause (e.g., within 5 years) is neutral or even beneficial for CVD, brain health, and dementia risk. 199 , 200 The route of MHT administration (oral vs transdermal) also matters. Oral estrogens undergo first‐pass hepatic metabolism, which can increase cardiovascular and inflammatory risks, whereas transdermal delivery bypasses the liver, avoiding these effects. 201 , 202 , 203 Accordingly, transdermal (vs oral) MHT has been associated with more favorable cognitive and brain outcomes. 204 , 205 MHT formulation may further influence CVD and dementia risk. Estradiol MHT has been associated with lower CVD and dementia risk compared to conjugated equine estrogens, a formulation of weaker estrogens used in the WHI. 206 , 207 , 208 Additionally, estrogen‐only formulations are associated with lower CVD and dementia risk than combined estrogen and progesterone formulations. 55 , 170 , 198 However, combined formulations are necessary for women with an intact uterus to reduce the risks of endometrial hyperplasia and endometrial cancer. 162 Emerging evidence suggests that genetic factors may further modify the effects of MHT. Apolipoprotein E ( APOE) ε4, a strong genetic risk factor for both CVD and late‐onset AD, 209 may interact with chromosomal and endocrine aspects of sex biology. 210 Two studies reported that MHT use was associated with improved cognition, less brain atrophy, and lower levels of AD pathology in APOE ε4 carriers, but not in non‐carriers. 211 , 212 A recent meta‐analysis reported the opposite pattern, such that MHT was associated with reduced dementia risk in APOE ε4 non‐carriers, but not carriers. 213 These conflicting findings highlight the complex interplay between endocrine factors, genetic risk, CVD, and AD/ADRD. Hormonal contraceptives are generally safe and effective for pregnancy prevention and offer several non‐contraceptive benefits, such as the treatment of menstrual cycle irregularity, heavy menstrual bleeding, premenstrual syndrome, perimenopausal vasomotor symptoms, acne, and hirsutism. 2 , 214 While the absolute risk of CVD associated with hormonal contraceptive use remains low in women overall, 2 , 214 it is higher among older individuals as well as those with pre‐existing CVD risk factors such as smoking, hypertension, diabetes, and obesity. 2 , 215 Since the early 2000s, it has become more common for healthcare providers to screen for CVD risk factors before prescribing hormonal contraceptives. 216 As a result, women using hormonal contraceptives today likely have a lower baseline risk for CVD compared to users in earlier decades. 214 Very little research has examined the potential links between a history of hormonal contraceptive use and dementia. Some studies suggest that prior use of oral contraceptives is associated with a lower risk of dementia, while others have found no significant associations. 182 , 217 , 218 , 219 However, these studies are typically observational and retrospective, which may not adequately mitigate confounding. Data on the use of non‐oral hormonal contraceptive options and their effects on cardiovascular and brain health are limited, with existing evidence suggesting no significant associations with CVD outcomes. 154 Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, 220 affecting 5% to 18% of women. 221 PCOS is characterized by excess androgens and infrequent or irregular menstrual periods. 220 Adverse metabolic features are well documented in PCOS, particularly insulin resistance, which can be exacerbated by higher BMI. 222 Other common features include diabetes, hypertension, dyslipidemia, and depression. 223 , 224 These CVD risk factors tend to appear earlier in women with PCOS compared to the general population. 225 Despite the strong links between PCOS and CVD, associations of PCOS with dementia remain underexplored. Limited data suggest that women with PCOS perform worse on cognitive tests compared to non‐PCOS controls 226 and may be at increased risk of AD/ADRD later in life. These associations may be driven by factors such as altered insulin and/or androgen signaling in the brain, chronic inflammation, and cerebrovascular changes. 227 For example, a recent study in the CARDIA cohort reported that women with PCOS had lower cognitive performance and worse white matter integrity at midlife compared to women without PCOS. 228 Endometriosis is a chronic gynecological condition defined by the growth of tissue similar to the endometrium outside the uterus. 229 Endometriosis affects approximately 1 in 10 women of reproductive age and can lead to inflammation, pain, and fertility issues. 229 Studies report that individuals with endometriosis are at higher risk for hypertension, high cholesterol, earlier menopause, and autoimmune conditions. 229 , 230 , 231 , 232 There are currently no known data on the associations between endometriosis and dementia.

Autoimmune disorders are a heterogeneous group of conditions that show striking sex differences, with women accounting for approximately 80% of all cases. 233 Most autoimmune disorders are associated with an increased risk for CVD, including Grave's disease, Hashimoto's thyroiditis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. 234 The sex disparity in autoimmune disorders is thought to result from a combination of factors including chromosomal composition, reproductive organs, and sex hormones, which contribute to more robust innate and adaptive immune responses in women compared to men. 233 Despite these sex differences, very limited research has investigated whether associations between autoimmune conditions and CVD vary by sex. One recent study found that Addison's disease disproportionately increased the risk for ischemic heart disease in women relative to men, 235 while another study suggested that inflammatory joint conditions generally increase CVD risk more strongly in men than in women. 236 Research also points to a connection between autoimmune disorders and dementia, with elevated risks observed for both AD and vascular dementia. 234 , 237 , 238 , 239 , 240 Chronic inflammation may be a key mechanism underlying the links between autoimmune disorders, CVD, and dementia. 234 , 241 While sex‐specific research in this area is limited, emerging evidence suggests that inflammatory processes may contribute more strongly to AD pathogenesis in women relative to men. 242 However, findings on sex differences in autoimmune‐associated dementia risk are limited. One recent large study reported that autoimmune disorders were associated with a greater risk for AD dementia in women and a greater risk for vascular dementia in men. 243 Another study found that autoimmune disorders increased the risk of dementia more strongly in men than women, 239 while a separate study reported the opposite pattern. 240 Depression increases the risk of CVD, with studies showing a clear link between the two conditions. 244 Women are diagnosed with depression twice as frequently as men and experience higher rates of severe symptoms, comorbid anxiety, and atypical features like weight gain and fatigue. 245 These sex differences extend to distinct immune profiles and brain abnormalities. 245 However, research on sex‐specific CVD risks associated with depression shows mixed results. One study of young adults found that heart rate variability (i.e., a biomarker of autonomic regulation of cardiac function) was reduced in men but not in women with depression. 246 Cross‐sectional data from adults in the United States National Health and Nutrition Examination Survey (NHANES) showed that the association between depressive symptoms and CVD outcomes was significantly stronger in women than in men. 247 Depression is also an established risk factor for cognitive decline and dementia. 248 Despite higher rates of both depression and AD in women, some studies investigating sex differences in the relationship between depression and dementia point to stronger associations in men compared to women, 249 , 250 , 251 , 252 , 253 though the reverse pattern has also been reported. 254 , 255 , 256 These conflicting findings may relate to differences in depressive symptom severity, given findings that mild depressive symptoms were associated with cognitive impairment in men, whereas moderate and severe depressive symptoms were associated with cognitive impairment in women. 257 Regarding brain outcomes, a longitudinal study of approximately 1,300 older adults reported that both lifetime history of depression and baseline depressive symptoms were associated with smaller hippocampal volumes and faster hippocampal volume loss in women, but not in men. 258 A small cross‐sectional study observed that depressive symptoms were associated with white matter hyperintensities and infarcts in women, but not in men. 259 Conversely, a small longitudinal study found that depressive symptoms were associated with increases in white matter hyperintensity burden in men, but not in women. 260 Limited research has examined sex‐specific effects of depression in AD pathology outcomes, with one study finding no evidence of sex differences. 261 Approximately one in eight women will develop breast cancer in their lifetime, 262 and 99% of all breast cancers occur in women. 263 Compared to women with no history of breast cancer, breast cancer survivors have a higher risk of CVD, especially cardiomyopathy, heart failure, and CVD‐related mortality. 264 , 265 , 266 , 267 These associations are partly due to the cardiotoxic effects of many common breast cancer treatments (i.e., anthracycline chemotherapy and radiotherapy), which are known to cause systolic dysfunction, arrhythmias, and other adverse cardiac effects. 262 Endocrine therapies, used to reduce estradiol levels in hormone receptor‐positive breast cancers, may further contribute to increased CVD risk in breast cancer survivors. 268 Beyond treatment effects, several shared risk factors contribute to both CVD and breast cancer, including advanced age, smoking, obesity, and physical inactivity. 262 , 269 Hormonal factors also influence both CVD and breast cancer risk. For example, earlier age at menopause increases CVD risk 117 but is associated with lower breast cancer risk. 270 Furthermore, both MHT and hormonal contraceptives have effects on cardiovascular health (as detailed earlier), and both are associated with small increases in absolute risk for breast cancer. 271 , 272 In terms of dementia risk, findings are mixed. Some studies report that breast cancer survivors are at greater risk for AD dementia, 273 , 274 while others suggest a lower risk of dementia. 275 , 276 A similar pattern of reduced dementia risk has been observed in survivors of other cancers, 277 and this may not be fully explained by survivor bias. 278 , 279 These conflicting findings might partly reflect differences in treatment exposures and their potential impact on brain health. For example, research shows that breast cancer survivors who receive endocrine therapies (especially aromatase inhibitors and tamoxifen) have a lower risk of dementia compared to those who do not. 280 , 281 , 282 While these treatments reduce systemic estrogen levels and block its actions in breast tissue, they may act as estrogen agonists in the brain, providing potential neuroprotective effects. 283 By contrast, chemotherapy has been associated with reduced frontal gray matter volumes and declines in cognitive performance in women with breast cancer, 284 , 285 but it remains unclear whether these changes are long‐lasting and increase dementia risk over time. 286

Supporting Information