Sex and gender differences in the causes of dementia: A narrative review

Abstract

This is a narrative review of new ideas and concepts related to differences between men and women in their risk of developing dementia or Alzheimer's disease (AD). We introduce the concept of dimorphic neurology and the distinction between sex and gender. We then provide three examples of risk factors related to sex and gender from the literature. Apolipoprotein E genotype is equally common in men and women but has a stronger effect in women. Apolipoprotein E genotype is a biological factor that cannot be modified but interacts with sex or gender related factors that can be modified. Low education has a similar harmful effect in men and women but has been historically more common in women. Education is a social factor related to gender that can be modified. Finally, bilateral oophorectomy is a factor restricted to women. Bilateral oophorectomy is a surgical practice related to sex that can be modified. Consideration of risk and protective factors in men and women separately may accelerate etiologic research for neurological diseases in general, and for dementia and AD in particular. Similarly, future preventive interventions for dementia should be tailored to men and women separately.

Introduction

We have observed two important conceptual trends in the last 20 years that will contribute to our future understanding of the risk of developing dementia or Alzheimer's disease (AD). First, there is increasing attention to differences between men and women in the causes, manifestations, response to treatments, and outcomes of neurological diseases (dimorphic neurology) [1], [2], [3], [4], [5]. This attention to dimorphic medicine has historically been stronger in fields like cancer, cardiovascular diseases, and endocrine diseases [1], [6], [7]. However, there is now a growing awareness of differences in brain structure and function between men and women throughout the entire life course (early childhood development, adult life, and aging) [2], [3], [8], [9]. Second, there is increasing recognition of the distinction between sex and gender. Sex is biology: chromosomal, hormonal, or reproductive differences between men and women [1], [4], [5]. By contrast, gender refers to psychological, social, political, and cultural differences between men and women [4], [5], [10]. These two conceptual trends are likely to transform our approach to identifying risk factors for dementia or AD.

Dementia is one of the most common diseases related to aging, and its impact on society is growing with time because of the rapid aging of populations worldwide [11], [12]. It remains unclear whether women have a higher risk than men to develop dementia or AD at a given age [12], [13]. Several European studies have suggested that women have a higher incidence rate of dementia or AD than men. However, studies in the United States have not shown a difference, or the difference has varied with age [12]. Regardless of this difference in risk (in incidence rates) across continents, all studies consistently showed that more women than men have AD at any given age, possibly because women survive longer [11], [14], [15]. However, the higher number of women affected by dementia may not be true for other types of dementia such as vascular dementia or Lewy body dementia.

It is important to distinguish sex and gender for the understanding of risk and protective mechanisms of disease. The US Institute of Medicine clarified the difference between sex and gender in a 2010 report: “Sex” refers to the classification of living things as male or female according to their reproductive organs and functions assigned by chromosomal complement, and “gender” refers to a person's self-representation as male or female or to how that person is responded to by social institutions on the basis of that presentation [5]. Thus, sex refers to biological characteristics of men and women, such as chromosomal differences (e.g., XX vs. YY chromosomes), hormonal differences (e.g., effects of estrogen or testosterone), or reproductive differences (e.g., pregnancy or menopause) [1], [4], [5].

Limited attention has been given to the sex chromosomes in relation to the etiology of diseases in general and of dementia or AD in particular [16]. Women have two copies of chromosome X, one of maternal origin and one of paternal origin. The X-chromosome carries approximately 1600 genes (approximately 155 million base pairs), including genes encoding the androgen receptor and several proteins involved with mitochondrial function, adipose tissue distribution, apoptosis, and response to hypoxia [16], [17]. To avoid a genetic overdose, most of the genes encoded on one of the two X-chromosomes are inactivated in female cells [17], [18], [19].

We are now discovering that women are not only complex mosaics of cells with paternal X or maternal X chromosome expressed, but that this mosaic pattern varies from organ to organ (e.g., liver vs. retina vs. brain) and within organs (e.g., hippocampus vs thalamus vs cerebral cortex). Of particular interest to brain functioning, the mosaic pattern of X-chromosome inactivation may vary on a spatial scale from neighboring cells to the left versus the right side of the brain. For example, the right and left hippocampi of a mouse brain (and probably of a woman's brain) may have different amounts and patterns of paternal and maternal X-chromosome inactivation [20], [21]. Therefore, patterns of X-chromosomes inactivation may give a new perspective on the concept of laterality of brain functions in women compared with men. This mosaic pattern of X-chromosome inactivation varies from woman to woman. In addition, the mosaic pattern has been shown to change over the lifespan of female mice [22], and could, conceivably, change also in women.

In contrast to sex, gender includes both a subjective component of self-representation (or sexual identity) and societal components related to the social, cultural, and legal contexts in which women live. For example, a woman may rate herself higher or lower on a masculinity vs. femininity personality scale [23]. However, her right to drive a car, vote for political elections, or own property will depend on the legal system of the country in which the woman lives in a given point in history (e.g., Sweden vs. Saudi Arabia). The personal aspects of gender (e.g., psychology, personality, or behavior) are linked with the social and political aspects (e.g., legal system, religious practices, or local traditions), and it is sometimes difficult to determine to which extent the self-representation of gender is the determinant or the consequence of cultural, political, or religious norms. Thus, sex and gender are tightly related and interdependent; however, they are not the same. Each variable should be studied independently [7], [23].

Gender-related factors have also varied over history. For example, women in the United States were not allowed to vote until the passage of the Nineteenth Amendment to the United States Constitution in 1920 (Women's Suffrage). Similarly, women in the United States have been less likely than men to smoke cigarettes during most of the 20th century. The gap in smoking behavior is now narrowing [12], [24].