Michelle M. Mielke, PhD

Alzheimer disease (AD) dementia is the most common form of dementia, comprising 60% to 70% of all cases. AD is a progressive neurodegenerative disease that causes memory loss, cognitive deficits, and behavioral changes. The hallmark characteristics of AD include the presence of extracellular amyloid-beta plaques, intracellular neurofibrillary tangles, and neurodegeneration. With the aging of the population, the burden of AD dementia is growing to epidemic proportions. More than five million people in the US have a diagnosis of AD, and it is estimated that by 2050 14 to 16 million will have a diagnosis unless new treatments or interventions to prevent or delay the onset of AD are identified.

 A declining trend in the risk of dementia has been reported for several high-income countries in the past 20 to 30 years. The impact of these trends on the future remains uncertain, however, and it is not clear what type of dementia may be driving these trends.

Precision medicine techniques and approaches have emerged over the last decade that have advanced our understanding of the pathophysiological changes associated with the development and progression of AD dementia. However, the examination of sex and gender differences has not been well integrated into these approaches. This is surprising given the extensive literature demonstrating sex differences in brain structure and function over the lifespan.

Several misconceptions also exist about the study of sex and gender in the AD field. The initial focus of this article is on whether women are at greater risk. A few examples of risk factors for AD that differ by sex are provided, followed by an overview of potential differences in comorbid neuropsychiatric symptoms. Throughout, we utilize the definitions of sex and gender from the Institute of Medicine.

 Sex refers to the biological and physiological differences between women and men, with the sex chromosomes (X and Y) contributing to these differences. Gender refers to a combination of environmental, social, and cultural influences on women and men. Gender is rooted in biology, but it is primarily shaped by environment and experience.

Are women at greater risk for AD dementia?

Historically, the primary reason stated for examining sex or gender differences in AD dementia is that “women are at greater risk” and that there is a need to understand what factors contribute to the greater risk for women. This rationale needs to be reassessed. About two-thirds of persons with a diagnosis of AD dementia are women.

 However, life expectancy for women is longer than for men, and age is the greatest risk factor for AD dementia. As a result, and similar to other aging-related diseases, the lifetime risk of AD dementia is greater for women. Although the incidence of AD dementia is higher in women, sex differences in the incidence of AD dementia are less clear.

In the US, study data overwhelmingly show that the incidence of AD dementia does not differ by sex, even after the age of 85 years.3 In other areas of the world, however, women appear to have a higher incidence. Findings from studies in several European countries indicate that women have a higher incidence of AD dementia after the age of 80.

 Nevertheless, the Cognitive Function and Aging Study in the United Kingdom, however, initially reported a higher incidence for men.

The reasons for these discrepancies are not well understood but suggest that sex and gender differences in the incidence of AD dementia may depend on the period of time and geographic region. For example, the experiences of World Wars I and II were vastly different in European countries compared with the US and in men compared with women. Further study of these worldwide differences is needed and would provide an opportunity to identify modifiable risk factors for AD dementia. Notably, these studies also highlight the fact that AD is not a disease unique to women, but that many men are also affected.

Sex and gender differences in risk factors for AD dementia

Even if women and men have the same incidence of AD dementia (age- and sex-specific incidence rate), the mechanisms, pathways, and risk factors can still differ. Many studies examining risk factors for AD adjust for sex in the analyses but do not determine whether there are actual sex differences (ie, whether the strength of the association between a risk factor and AD dementia differs by sex). There are multiple scenarios by which sex and gender differences could affect the risk of AD dementia (

Examples of sex differences in risk factors.

 Compared with men, women have twice the risk for depression.

 Depression has implications for cognition across the lifespan because mood and memory map to some of the same brain regions. Studies report that depression is a risk factor for AD dementia in both women and men. Estimates range as high as a 70% increased risk of AD dementia for those with depression in midlife.

 Therefore, because the lifelong prevalence of depression is greater in women, a diagnosis of depression may have a greater overall impact for AD dementia risk among women.

In contrast to depression, men have a greater overall prevalence of sleep apnea, although the prevalence of sleep apnea in women significantly increases after menopause.

 Sleep apnea and poor sleep quality have been associated with cognitive decline and an increased risk of AD dementia. Given that men have a higher prevalence of sleep apnea, the effect of this risk factor may have a greater overall impact in men. Notably, there is a lack of studies examining whether the association between sleep apnea and AD dementia differs by sex.

Examples of gender differences in risk factors.

 Lower levels of education have consistently been associated with an increased risk of AD dementia for both women and men. Historically, women have had fewer opportunities for higher education. Therefore, the risk of AD dementia attributable to lower level of education has been greater for women. One study suggested that a lower level of education may have a stronger deleterious effect for AD dementia in women, independent of their access to education.

 More recently, educational attainment for women has been higher than that for men in the US. The progressive improvement in education in women over the last century may be one explanation why the incidence of dementia may be declining more for women than men.

Men who have never married or are widowed are at increased risk for AD dementia compared with women.

 A possible reason is that women have historically been responsible for the health care of their family (eg, getting partners/husbands to health care providers for regular check-ups, assuring a healthy diet), sometimes at the expense of their own health. Compared with single men, single women are more likely to see a health care provider and to engage in social activities, which are beneficial for cognition. Although these observations are a bit stereotypical and not true in all situations, they may explain part of the difference in risk.

 Hypertensive pregnancy disorders (HPD) affect approximately 12% of all pregnancies. A history of HPD has been associated with an increased risk of brain atrophy and cognitive decline decades after the pregnancy.

 However, the association between HPD and specific types of HPD and the risk of AD dementia has not been examined. The menopausal transition has been associated with a decrease in verbal memory, and early menopause (eg, either natural or surgical) has been associated with an increased risk of dementia.

 In particular, premenopausal bilateral oophorectomy resulting in the abrupt loss of ovarian hormones has been associated with both an increased risk of dementia and accelerated aging.

There is still much debate regarding the use of estrogen-containing hormone therapies and type (eg, conjugated equine estrogens versus 17Î²-estradiol patch) for mitigating the risk of AD dementia in women. Although initial results from the Women’s Health Initiative Memory Study suggested that women who were randomized to start taking estrogen therapy after the age of 65 years were at greater risk of dementia, recent clinical trials and observational studies have not found an association with cognitive decline or dementia risk when hormone therapy is initiated within 5 years of menopause.

 Findings indicate that it is safe to treat menopausal symptoms without worrying about an increased risk for dementia. Nevertheless, additional research is clearly needed.

Androgen-deprivation therapy (ADT) is now used for more than one-half of all men with prostate cancer at some stage after diagnosis.18 Some studies suggest that ADT is associated with cognitive decline and risk of dementia. Additional studies are needed to determine the long-term effects of ADT for risk of dementia in men.

Most patients with AD dementia experience neuropsychiatric symptoms at some point during the course of the disease. These symptoms lead to poorer medical and functional outcomes as well as increased caregiver burden. Recent studies suggest that the distribution of neuropsychiatric symptoms may vary by sex. In a study of patients with newly diagnosed AD dementia who were not treated for AD or neuropsychiatric symptoms, women had a higher mean Neuropsychiatric Inventory score for depression, anxiety, and total neuropsychiatric symptoms.

Findings from another study indicate that women with AD dementia have higher depressive symptoms, whereas men are more likely to have agitation.20 Better characterization of the sex differences in neuropsychiatric symptoms among AD dementia patients will help to elucidate sex differences in the disease pathophysiology and to identify better treatment targets for women and men.

The study of sex and gender differences in the AD field is in its infancy compared with other areas of medicine such as cardiology. Research in the field of cardiology has shown that there are sex and gender differences in risk factors, symptom presentation, mortality, and treatment response for cardiovascular diseases. Better understanding of these sex and gender differences has led to improved care and treatment for both women and men.

The same positive outcome can occur for the prevention and treatment of AD dementia. We must move beyond the notion that women are at greatest risk and that AD dementia is a women’s disease to focus on sex and gender differences.

This overview provided a few scenarios of sex and gender differences in risk factors for, and clinical presentation of, AD dementia. There will not be sex or gender differences in all risk factors or mechanisms. Identifying where there are differences, however, will provide better treatment and care for both women and men.

This work was supported by RF1 AG55151 and U54 AG44170.

Dr Mielke is Professor, Department of Health Sciences Research, Division of Epidemiology and Department of Neurology, Mayo Clinic, Rochester, MN. Dr Mielke reports that she serves as a consultant to Eli Lilly and Lysosomal Therapeutics, Inc. She receives research support from the NIH (R01 AG49704, U54 AG44170, U01 AG06786, RFI AG55151), the Department of Defense (W81XWH-15-1), and unrestricted research grants from Biogen and Lundbeck.

 Alzheimer Association. Alzheimer disease facts and figures. 

Exploring the Biological Contributions to Human Health: Does Sex Matter?

 Washington, DC: National Academies Press; 2001.

 Edland SD, Rocca WA, Petersen RC, et al. Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, MN. 

 Fratiglioni L, Viitanen M, von Strauss E, et al. Very old women at highest risk of dementia and Alzheimer disease: incidence data from the Kungsholmen Project, Stockholm. 

 Letenneur L, Gilleron V, Commenges D, et al. Are sex and educational level independent predictors of dementia and Alzheimer’s disease? Incidence data from the PAQUID project. 

 Matthews FE, Stephan BC, Robinson L, et al. A two-decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. 

 Kessler RC, McGonagle KA, Swartz M, et al. Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. 

 Goveas JS, Espeland MA, Woods NF, et al. Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women’s Health Initiative Memory Study. 

 Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. 

 Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. 

 Russ TC, Stamatakis E, Hamer M, et al. Socioeconomic status as a risk factor for dementia death: individual participant meta-analysis of 86 508 men and women from the UK. 

 Pankratz VS, Roberts RO, Mielke MM, et al. Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging. 

 Mielke MM, Milic NM, Weissgerber TL, et al. Impaired cognition and brain atrophy decades after hypertensive pregnancy disorders. 

 Epperson CN, Sammel MD, Freeman EW: Menopause effects on verbal memory: findings from a longitudinal community cohort. 

 Rocca WA, Grossardt BR, Shuster LT: Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. 

 Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. 

 Gleason CE, Dowling NM, Wharton W, et al. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS-Cognitive and Affective Study. 

 Barry MJ, Delorenzo MA, Walker-Corkery ES, et al. The rising prevalence of androgen deprivation among older American men since the advent of prostate-specific antigen testing: a population-based cohort study. 

 Spalletta G, Musicco M, Padovani A, et al. Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. 

 Lee J, Lee KJ, Kim H: Gender differences in behavioral and psychological symptoms of patients with Alzheimer disease. 

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Several misconceptions exist about the study of sex and gender in the AD field. The initial focus of this article is on whether women are at greater risk.

Michelle M. Mielke, PhD

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