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Review
. 2021 Jun;78(11):4907-4920.
doi: 10.1007/s00018-021-03830-w. Epub 2021 Apr 12.

Alzheimer's pathogenic mechanisms and underlying sex difference

Donghui Zhu  1   2 , Axel Montagne  3   4 , Zhen Zhao  5   6
Affiliations
Review

Alzheimer's pathogenic mechanisms and underlying sex difference

Donghui Zhu et al. Cell Mol Life Sci. 2021 Jun.

Abstract

AD is a neurodegenerative disease, and its frequency is often reported to be higher for women than men: almost two-thirds of patients with AD are women. One prevailing view is that women live longer than men on average of 4.5 years, plus there are more women aged 85 years or older than men in most global subpopulations; and older age is the greatest risk factor for AD. However, the differences in the actual risk of developing AD for men and women of the same age is difficult to assess, and the findings have been mixed. An increasing body of evidence from preclinical and clinical studies as well as the complications in estimating incidence support the sex-specific biological mechanisms in diverging AD risk as an important adjunct explanation to the epidemiologic perspective. Although some of the sex differences in AD prevalence are due to differences in longevity, other distinct biological mechanisms increase the risk and progression of AD in women. These risk factors include (1) deviations in brain structure and biomarkers, (2) psychosocial stress responses, (3) pregnancy, menopause, and sex hormones, (4) genetic background (i.e., APOE), (5) inflammation, gliosis, and immune module (i.e., TREM2), and (6) vascular disorders. More studies focusing on the underlying biological mechanisms for this phenomenon are needed to better understand AD. This review presents the most recent data in sex differences in AD-the gateway to precision medicine, therefore, shaping expert perspectives, inspiring researchers to go in new directions, and driving development of future diagnostic tools and treatments for AD in a more customized way.

Keywords: Aging; Cognition; Dementia; Estrogen; Gender difference; Hormones; Menopause.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Estimated Lifetime Risk for AD by Sex at Ages 45 and 65. (Reprinted/adapted with permission from [1])
Fig. 2
Fig. 2
Vascular hypothesis explaining the link between vascular dysfunction and AD. (Reprinted/adapted with permission from [116])
Fig. 3
Fig. 3
Models of menopause in rodents and human. (Reprinted/adapted with permission from [91])
See this image and copyright information in PMC

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