Why are women twice as likely as men to develop Alzheimer’s disease (AD)?


Epidemiological studies have shown that women are twice as likely as men to develop Alzheimer’s disease (AD), but the cause of this phenomenon has been unclear.

Now, however, a study led by Prof. Keqiang Ye from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences provides a clear answer to this mystery that has puzzled mankind for decades.

Their findings were published in Nature on March 2.

Integrating their previous studies, Prof. Ye’s team has established the theory that the C/EBPβ/AEP pathway is the core factor driving the pathogenesis of neurodegenerative diseases.

“Based on this theory, our team searched for female hormones that are dramatically changed during menopause and tested which hormone selectively activates the C/EBPβ/AEP pathway,” said Prof. Ye.

Prof. Ye’s team identified follicle-stimulating hormone (FSH) as the major pathogenic factor.

“During menopause, the serum concentration of FSH strongly increases, binding to the cognate FSH receptor on neurons and activating the C/EBPβ/AEP pathway.

This results in Aβ and Tau pathologies, leading to the development of AD,” said Dr. Zaidi Mone, co-corresponding author of the study and a tenured professor at the Mount Sinai School of Medicine in New York.

The researchers employed different methods to demonstrate this finding. Using ovariectomized mice, they used anti-FSH antibody treatment to block FSH and inactivate the C/EBPβ/AEP pathway. They also deleted FSH receptor (FSHR) expression in neurons to abolish the binding of FSH to FSHR in the hippocampus. Both of these methods alleviated pathology and cognitive dysfunction. In addition, knockdown of C/EBPβ in the AD mice model decreased AD pathologies.

Besides working with female mice, the researchers also injected FSH into male mice and discovered that FSH promoted AD pathologies.

All these findings suggest that increased FSH after menopause binds to FSHR in neurons and activates the C/EBPβ/AEP pathway, which plays an important role in triggering AD pathology.

In the near future, the team will focus on dissecting the relationship between specific risk genes such as ApoE4 and FSH to explore why female ApoE4 carriers are more vulnerable to developing AD.

“Our findings demonstrate that the C/EBPβ/AEP signaling pathway acts as a core factor in these age-dependent diseases, which may help disclose how a variety of risk factors mediate neurodegenerative diseases via activating this pathway,” said Dr. Seong Su Kang from Emory University.

In addition, Prof. Ye’s team is extending this theory to numerous age-dependent chronic diseases such as diabetes, atherosclerosis, cancer, and aging.

Alzheimer disease (AD) is a progressive neurodegenerative disorder causing memory loss, cognitive deficits, and behavioral changes. The hallmark physiopathological features of AD include β-amyloid plaques, neurofibrillary tangles, and neuronal lesions that cause a disruption of metabolic processes leading to a progressive cognition impairment [1]. AD represents 60–80% of all dementia cases, with an estimated overall prevalence of 4.4% among individuals aged 65 years and older [2].

Prevalence increases with advancing age (0.97% for 65–74 years, 7.7% for 75–84 years, and 22.5% for ≥ 85 years) and is significantly higher in elderly women (7.1% in females vs. 3.3% in males) [3]. AD and other dementias are the fifth leading cause of death, killing 2.4 million people globally [4]. In Spain, AD caused a total of 14,929 deaths in 2018, with 10,475 of them occurring in women, accounting for a 5% of overall female mortality [5].

Mild cognitive impairment (MCI) is a transitional clinical entity between normal aging and dementia [6], with about 10–15% of all cases progressing yearly to clinically probable Alzheimer dementia [7]. MCI prevalence ranges from 16 to 20% in patients aged 50 or older, but as opposed to dementia, the evidence of any gender-based differences is unclear [8].

Because the incidence of AD is strongly associated with age, it is expected that population aging as well as the current lack of effective disease-modifying strategies will contribute to an increasing trend in its prevalence that will pose huge challenges to public healthcare systems across the world [9].

Sex- or gender-based differences in the prevalence of AD are not entirely explained by the increased longevity of women, but also by biological or sociocultural differences found between men and women that account for heterogeneity in risk factors, cognitive decline, prognosis, and drug effects [10,11,12]. The AD phenotype and progression pattern is affected by well-known sex-related (referring to biological variations among men and women) as well as gender-related differences (referring to psychosocial and cultural disparities between males and females) with crucial implications for diagnosis, treatment and clinical research [13].

Sex-specific patterns were reported in the rate of cognitive decline and brain atrophy, in the effects of risk factors as well as in the patterns of diagnostic biomarkers [12]. This variability in disease presentation might indicate differential neuropathological mechanisms operating in men and women. In this regard, women with AD report faster hippocampal atrophy rates and higher prevalence of neurofibrillary tangles and amyloid plaques [14].

The APOE4 allele for instance, a genetic factor for late-onset AD, confers greater risk for developing the disease in women. Hormonal changes (mainly estrogens) linked to woman’s reproductive system, as well as the excess risk of thyroid disease observed in women, have also been associated with higher risk of AD [15].

Sex differences were also found in the rates comorbidities and the use of drugs in AD patients. Depression, anxiety, thyroid disease, autoimmune disorders, and chronic pain, which in turn lead to the use of psychotropics, hormonal drugs, immunosuppressants, or opioids among others, were more frequently reported in women [12].

These conditions often involve a disruptive effect on cognitive function and consequently lead to a higher risk or a worse prognosis of AD. Furthermore, understanding the interaction of sex on the effects of anti-dementia drugs may also have important implications for women’s health. Anti-dementia therapies with suboptimal safety/efficacy evidence in women may in fact increase the risk of poorer outcomes or adverse effects in the female population with AD. However, despite this, few studies thus far provide sex-disaggregated data [16].

A well-known gender-related factor affecting AD is cognitive activity. Low cognitive activity has been associated with a higher risk of developing of AD [17] as well as a longer duration of the disease [18]. In the past, men have had more opportunities for better education and higher occupational status than women, and thus, particularly in the older aged groups (≥ 70 years), women are at higher risk of presenting AD [19].

However, intellectual lifestyles in women have changed which may transform the epidemiological patterns of dementia in the near future. Another gender-associated factor indirectly reverting the burden of AD on women is the use of caregivers. An estimated 71% of all dementia patients have a caregiver [20], and approximately two thirds of them are women [1].

Women underrepresentation in clinical research is a persistent problem according to a study involving 43,000 published research studies and 13,000 registered clinical trials over 25 years [21]. Average women enrolment across studies is close to 50%; however, for many disease types, women participation is not proportional to the burden of the disease. Furthermore, according to a report from the Spanish Agency of Medicines, only 20% of the trials present sex-disaggregated efficacy or safety data [22].

In a systematic review considering 48 AD studies and a total of 20,688 patients, the overall proportion of women was 63.8%, with nearly all trials recruiting a larger number of women, but minimal information on the potential effect of sex on treatment efficacy or tolerability [16]. According to this report, women participation mirrored the sexually unbalanced prevalence of AD; however, this estimate was below that found the population living with the disease.

Previous reports also revealed significant discrepancies in the gender distributions of AD trial participants and the general population (63.2% versus 67.8% respectively) [23]. The representativeness of women in AD research is therefore arguable, more importantly because they are the primary users of anti-dementia drugs.

A proportional participation of women in clinical trials is key to warrant the external validity of findings, allowing for a better understanding of drug effects in men and women, ultimately leading to improved tolerability and clinical outcomes. However, thus far, the relevance of sex as interacting factor on the efficacy and safety of anti-dementia therapies has received limited attention with scarce sex-disaggregated evidence on the effects of drugs [16] and no reports to date analyzing the potential causes of gender imbalances in trial enrolment.

Building on this background, we have designed a cross-sectional study aiming to identify the role of sex in the eligibility for participation in dementia trials and to analyze the causes of any found disparities between men and women. To this end, a cohort of 9593 patients with AD dementia or MCI was analyzed according to a set of pre-screening criteria currently applied at Fundació ACE memory clinic for a more efficient trial enrolment process. The distribution of men and women screened for trial enrolment over a period of 10 years was also assessed.

reference link :https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00833-4

Source: Chinese Academy of Science


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