How Sex and Gender Specific Risk Factors Influence Alzheimer’s Disease

To provide care for Alzheimer’s disease (AD) and other dementia patients, America’s total annual payments are projected to increase from 405 billion dollars in 2020, to more than 1.1 trillion dollars in 2050 (1). While our understanding of this illness has dramatically increased over recent years, there is still no available cure for AD. However, the intersections of sex and gender with AD can inform the development of future interventions and cures. In medical research, sex refers to biological differences such as chromosomal (eg, XX versus XY chromosomes), gonadal, or hormonal differences (2). In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation) (2). In order to maximize the development of AD treatments and interventions, it is important to understand how both sex- and gender-specific factors contribute to the disease. 

Cardiometabolic risk factors are one example of a sex-specific difference in risk factors for AD (3). Cardiometabolic diseases such as type 2 diabetes, metabolic syndrome, and obesity are all risk factors for AD (3). Women have a higher risk of cardiometabolic complications such as myocardial infarction, depression, high cholesterol, and diabetes (3). So while diagnosis of these factors are equally associated with AD for both women and men, women may have a greater overall risk for AD due to their greater tendencies to possess more cardiometabolic complications (3). Sex-specific risk factors for women, such as hypertensive pregnancy disorders, menopause and hormone therapy, may also their increase risk of AD, although more research is ultimately needed to better understand these relationships (3). 

Examples of gender and sociocultural risk factors for AD include lack of education and exercise. Low education and or low occupational history (unskilled versus skilled worker) increase risk of AD by lowering cognitive reserve (2). In the past century, men have had more opportunities for higher education and higher occupational attainment than women (2). This is particularly true for individuals aged 70 and older, who are now at the greatest risk for AD (3). As a result, more women than men are affected by this risk factor. Likewise, physical activity and cardiorespiratory fitness during midlife are associated with decreased risk of AD (3). It is estimated that American women tend to exercise less than men, with gender differences in parenting roles accounting for only some of this difference (3). As a result, for both of these sociocultural cases, women may be more disproportionately impacted (2,3).

In terms of genetics, the ε4 allele of the APOE gene is a major genetic risk factor of late-onset AD and is consistently linked with abnormal accumulation of Aβ protein (3). The apoE4 protein variant is less effective at Aβ clearance and contributes to a diminished response to neuronal injury (3). The risk of AD dementia is fourfold higher in women than that in men with the same APOE ε4 genotype. While the mechanisms between sex and the APOE genotype remain unclear, research suggests that APOE ε4 females may show greater levels of AD pathology, more compromised brain network integrity, and/or accelerated longitudinal decline for a given level of AD pathology (3).

Currently, neuroimaging and CSF biomarkers show great promise in elucidating the influence of sex and gender on AD pathophysiology (3). In fact, eye movement patterns can be elicited by physical, noninvasive examinations, and changes within these patterns can be linked with Alzheimer’s (4). Esurgi is developing Eye AD that utilizes specific patterns of saccadic eye movement to monitor and diagnose for the disease (5). It will also serve as a more objective and accessible tool that healthcare providers can use to hopefully achieve more accurate diagnosis and bridge sex and gender based differences (5). 

Sources:

1. alzheimers-facts-and-figures.pdf. Accessed September 6, 2020. https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf
2. Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol. 2014;6:37-48. doi:10.2147/CLEP.S37929
3. Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement. 2018;14(9):1171-1183. doi:10.1016/j.jalz.2018.04.008
4. Yang, Qing et al. “Specific saccade deficits in patients with Alzheimer’s disease at mild to moderate stage and in patients with amnestic mild cognitive impairment.” Age (Dordrecht, Netherlands) vol. 35,4 (2013): 1287-98. doi:10.1007/s11357- 012-9420-z. 
5. Panchal H, De A, Agbakwuruonyike C, Jiang Y, Kanjoo P. Literature Review on the Correlation Between Abnormalities in Eye Movement and the Presence of Alzheimer Disease. Published online 2020:7.