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Sex and Gender Driven Modifiers of Alzheimer’s: The Role for Estrogenic Control Across Age, Race, Medical, and Lifestyle Risks

Rahman A1Jackson H1Hristov H1Isaacson RS1Saif N1Shetty T2Etingin O3Henchcliffe C1Brinton RD4,5Mosconi L1,6,7.

Front Aging Neurosci. 2019 Nov 15;11:315. doi: 10.3389/fnagi.2019.00315. eCollection 2019.




Research indicates that after advanced age, the major risk factor for late-onset Alzheimer’s disease (AD) is female sex. Out of every three AD patients, two are females with postmenopausal women contributing to over 60% of all those affected. Sex- and gender-related differences in AD have been widely researched and several emerging lines of evidence point to different vulnerabilities that contribute to dementia risk. Among those being considered, it is becoming widely accepted that gonadal steroids contribute to the gender disparity in AD, as evidenced by the «estrogen hypothesis.» This posits that sex hormones, 17β-estradiol in particular, exert a neuroprotective effect by shielding females’ brains from disease development. This theory is further supported by recent findings that the onset of menopause is associated with the emergence of AD-related brain changes in women in contrast to men of the same age. In this review, we discuss genetic, medical, societal, and lifestyle risk factors known to increase AD risk differently between the genders, with a focus on the role of hormonal changes, particularly declines in 17β-estradiol during the menopause transition (MT) as key underlying mechanisms.

In conclusion, AD is a neurodegenerative disorder that has shown strong sex and gender differences in several aspects of the disease, including a faster onset of AD pathology and disease progression after diagnosis, and different risk factors that may account for the increased female prevalence of AD. This review article focused on the research dedicated to understanding the effects of estradiol in terms of gender and sex differences in AD, and the negative effects of MT as a tipping point for middle-aged women. The research findings presented range from studies on molecular mechanisms and preclinical models that clearly highlight estradiol’s interactions with a number of signaling and transcriptional pathways involved in cognition and memory, to neuroimaging studies that visualized ADrelated brain changes during the MT. Recent clinical trials and re-examinations of existing data lend support to the use of HRT as a possible risk reduction intervention in women at risk for AD, though more work is needed to examine this. Future research studies examining the underlying mechanism of estradiol’s neuroprotective action in AD are warranted. In order to address the growing AD epidemic, the field is shifting toward early detection and primary and secondary prevention efforts (Isaacson et al., 2018). It is crucial that these prevention and clinical trials take into account sex differences in AD biomarkers, disease progression, and gender differences with respect to modifiable risk factors to aid in the development of therapeutics for both men and women. Historically, women have been underrepresented in studies elucidating the underlying mechanisms of AD which has significantly impeded our understanding of gender differences (Mazure and Jones, 2015). Women still remain underrepresented in clinical trials of CVD, a known AD risk factor (Shen and Melloni, 2014). Future AD research studies should actively aim to increase women’s overall participation and analyze the influence of sex or gender on health outcomes. A better understanding of sex and gender differences is crucial toward the development of individualized AD risk reduction strategies and treatments.