Abstract
After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10–20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.
Highlights
Alzheimer’s Disease and the Importance of Being FemaleAlzheimer’s disease (AD) is the most common cause of dementia and the sixth leading cause of death in Western societies, affecting over 24 million patients worldwide (Alzheimer’s Association, 2021)
These shortcomings are attributable, at least in part, to the fact that most research has ignored the existence of biological sex differences in AD and focused on sex-aggregated risk
Given increasing evidence that AD prevalence, symptomatology, and risk profiles vary by sex (Mielke et al, 2014; Snyder et al, 2016; Ferretti et al, 2018; Rahman et al, 2019), a possible strategy to stem the AD epidemic is earlier intervention coupled with sex-specific interventions
Summary
Alzheimer’s disease (AD) is the most common cause of dementia and the sixth leading cause of death in Western societies, affecting over 24 million patients worldwide (Alzheimer’s Association, 2021). Knowledge of reproductive history effects on AD risk is critical to informing clinicians on management of modifiable factors for cognitive decline and for development of therapeutic targets that modify estrogenic risk factors Besides their obvious role in reproduction, sex hormones are known regulators of neuronal morphology, number, and function, which makes endocrine aging an important contributor to brain aging (McEwen, 1981; Behl, 2002; Arevalo et al, 2015). These studies implicate a shift in the bioenergetic system of the brain during the menopause transition as a trigger for Aβ deposition, along with increased fatty acid catabolism, and declines in mitochondrial activity and synaptic plasticity (Liu F. et al, 2008; Brinton, 2009; Yao and Brinton, 2012), which could serve as early initiating mechanisms for AD These data are consistent with evidence that 17β-estradiol promotes non-amyloidogenic processing by increasing secretion of amyloid precursor protein (APP) and decreasing Aβ production (Xu et al, 1998; Manthey et al, 2001; Nord et al, 2010). Pre-menopausal oophorectomies have been linked to alterations in nervous
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