Sex Differences in Cardiovascular Disease and Cognitive Impairment: Another Health Disparity for Women?

Although the number of Americans dying of cardiovascular disease (CVD) continues to increase since 2010 after decades of decrease, advances in the management of CVD have led to increased longevity among both women and men, with more people, mostly women, now surviving into their 80s and beyond.1 Paralleling this increased longevity, however, is an increasing prevalence of, and mortality from, neurodegenerative cognitive disorders.1 These cognitive disorders include dementia, a syndrome that has a multitude of causes and symptoms that ultimately have substantial impact on social and occupational activities and aspects of daily living.2 Typical symptoms of dementia include changes in memory, problem solving, language, and executive functioning.2 Although there are often distinct patterns, symptoms, and specific brain pathology associated with different dementias, multiple autopsy studies are now demonstrating that people with symptoms of a dementia will often have multiple brain pathologies noted at autopsy that were associated with the dementia.3, 4 Multiple reports document that approximately two thirds of those clinically diagnosed with Alzheimer dementia are women.5 Furthermore, it is estimated that by 2040 the number of Americans with some form of cognitive impairment (CI), including dementia, will be ≈8.3 million women and ≈3.3 million men.5 This sex‐related CI disparity is concerning and raises important questions about its possible relation to CVD and CVD‐related risk factor conditions. Although there are multiple types of dementia syndromes with different cognitive, behavioral, and pathological characteristics, the most common types are Alzheimer dementia and vascular cognitive impairment.6 Alzheimer dementia is characterized by an irreversible, progressive disorder that slowly destroys memory and thinking skills, and eventually the ability to perform simple tasks.7 Vascular cognitive impairment, a term that encompasses all levels of CI from its mildest form to vascular dementia, is characterized by progressive changes in behavior, function, and cognition caused by vascular injury (eg, strokes [infarcts], microbleeds [cerebral amyloid angiopathy and microhemmorhages]) or disease within the brain and includes deficits in executive functioning, attention, and language. This is in contrast to episodic memory deficits, which are more prominent in Alzheimer dementia. Increasingly, the term “mixed dementia” is used to describe the coexistence of both Alzheimer disease (AD) and vascular neuropathology in people experiencing dementia symptoms.8 In 2018, new criteria for AD were established by the National Institute on Aging and Alzheimer's Association to recognize that the disease occurs across a continuum of pathologic changes that precede its clinical manifestations and culminates with Alzheimer dementia.9 The clinical syndrome is noted as Alzheimer dementia, and the term dementia caused by AD is used when neuroimaging biomarkers or biofluid markers or autopsy confirm the diagnosis. This distinction continues to highlight the ongoing research that shows that AD begins many years before the symptoms of Alzheimer dementia are present.10 The term mild cognitive impairment (MCI) is used in people with demonstrable CI who have not crossed the threshold to dementia. MCI can refer to either a predominantly memory (amnestic) or nonmemory (nonamnestic) cognitive deficit and can be the initial symptom of a dementia syndrome, but it may also be secondary to other conditions or disease processes.11 A meta‐analysis revealed that women have a higher prevalence of nonamnestic MCI but suggested no sex‐related differences in the incidence or prevalence of amnestic MCI.12 At age 45 years, the lifetime risk for developing Alzheimer dementia is estimated at 1 in 5 for women versus only 1 in 10 for men.13 Possible reasons for this sex disparity, alone or more likely in combination, include greater longevity of women; their higher incidence of chronic diseases (particularly those CVD linked with CI), genetic predispositions, differences in cognitive testing performance (women outperform men on tests of verbal ability)14 (thereby potentially “masking” any underlying cognitive deficits, resulting in a later presentation to the healthcare provider for complaints of change in cognitive function), socioeconomic, psychosocial, and biological factors.15 Education level and occupational attainment (eg employment) can impact cognitive resilience and explain some of the sex disparities noted in dementia.16, 17 Traditionally, older women may not have had as many opportunities for attaining a higher level of education nor an equal period of time in the workforce compared with men, thus possibly putting them at an increased risk for developing cognitive decline and dementia. However, results from studies continue to be mixed, as methodological issues, study design, and comparability across studies remain difficult. Lastly, among the psychosocial factors, caregiving has emerged as a potential risk factor for developing dementia. Sex differences in spousal care are highly prevalent for patients with dementia, with women delivering the majority of the care and spending more time devoted to care.18 The increased stress of caregiving, coupled with lower levels of social support and poor physical health, are increasingly being examined as strong risk factors for cognitive decline and dementia in female caregivers. In addition to the aforementioned contributing factors of sex‐related differences in the dementia syndromes, this review examines sex differences in CVD and a broad range of CVD risk factors that may contribute to CI to explain, at least in part, the higher prevalence of dementias in women versus men. Potential implications of these sex differences are addressed in context for practitioners, our healthcare system, and related resource consumption. Important knowledge gaps are identified to direct the focus of future research. The American College of Cardiology CVD in Women Committee identified this topic and invited experts in the fields of CVD and/or CI to contribute sections in their respective fields. They did their own literature searches and submitted their sections to the chair of the writing committee (ASV), who compiled and summarized the sections to create a cohesive document. Over 300 selected publications were reviewed, and those addressing sex differences or new information were included in this document. This document is a summary of the topics that include stroke, microvascular or small‐vessel disease, and sex‐specific issues about differences in CVD that may help explain the increased prevalence of CI and dementia in women.