ReviewSex and gender differences in the causes of dementia: A narrative review
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].
Section snippets
Methods
This is a narrative review of new ideas and concepts that are developing regarding the etiology of dementia in men and women. Unfortunately, because different studies used different diagnostic categories, the data available specifically refer to AD in some studies and to dementia as a syndrome in other studies. More recently, the definition of dementia has expanded to include pre-clinical stages, such as mild cognitive impairment [25], [26], [27]. As a result, we are forced to use narrower or
APOE genotype and Alzheimer's disease
Traditional genetic studies that examined the association between single-nucleotide polymorphisms (SNPs) and AD, have normally considered sex as an adjustment variable. For example, case-control studies of individual SNPs, or their extension into genome-wide association studies of thousands of SNPs, have matched cases and controls by sex to avoid confounding. These analyses have not emphasized the role of sex as an effect modifier (interaction effect) because many studies did not have adequate
Conclusions
At this point in the history of research on the etiology of dementia or AD, we need new concepts, new theories, and new points of view rather than simply additional data. An impressive number of individual papers, monographs, books, literature reviews, and meta-analyses on the etiology of dementia or AD have been written [12]. It may be time to take some distance from the existing literature and see whether there are new lines of investigation to be explored.
We hope that this review will
Contributors
Walter A. Rocca drafted the manuscript. Michelle M. Mielke conducted an extensive literature review and reviewed the manuscript from an epidemiological perspective. Prashanthi Vemuri reviewed the manuscript from a brain imaging perspective. Virginia M. Miller reviewed the manuscript as an expert of sex and gender issues in medicine.
Competing interest
The authors declare no conflict of interest.
Funding
The authors receive funding from several NIH institutes (AG034676; AG006786; AG037526; AG044170).
Provenance and peer review
Commissioned and externally peer reviewed.
Acknowledgements
We would like to thank Ms. Carol J. Greenlee for her assistance in typing and formatting the manuscript.
References (65)
- et al.
eXclusion: toward integrating the X chromosome in genome-wide association analyses
Am J Hum Genet
(2013) - et al.
Cellular resolution maps of X chromosome inactivation: implications for neural development, function, and disease
Neuron
(2014) - et al.
The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement
(2011) - et al.
Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement
(2011) - et al.
Oophorectomy, estrogen, and dementia: a 2014 update
Mol Cell Endocrinol
(2014) - et al.
Time course of response to estradiol replacement in ovariectomized mice: brain apolipoprotein E and synaptophysin transiently increase and glial fibrillary acidic protein is suppressed
Exp Neurol
(2006) - et al.
Estradiol replacement increases the low-density lipoprotein receptor related protein (LRP) in the mouse brain
Neurosci Lett
(2007) - et al.
Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women
Neurosci Lett
(2000) - et al.
Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study
Lancet Neurol
(2006) - et al.
Mentally stimulating activities at work during midlife and dementia risk after age 75: follow-up study from the Kungsholmen Project
Am J Geriatr Psychiatry
(2009)