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Alzheimer’s pathogenic mechanisms and underlying sex difference

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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.

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Funding

This work was supported by National Institutes of Health [Grant number R01AG064798, R01HL140562, R01AG061288, R03AG063287, R21AG066090, R01NS110687]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

    Donghui Zhu

  2. Neuroscience Graduate Program, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA

    Donghui Zhu

  3. UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK

    Axel Montagne

  4. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    Axel Montagne

  5. Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Zhen Zhao

  6. Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Zhen Zhao

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  1. Donghui Zhu
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Zhu, D., Montagne, A. & Zhao, Z. Alzheimer’s pathogenic mechanisms and underlying sex difference. Cell. Mol. Life Sci. 78, 4907–4920 (2021). https://doi.org/10.1007/s00018-021-03830-w

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