Fresh Studies Illuminate the Role of Sex Hormones in Alzheimer’s Disease

Recent investigations have demonstrated that female sex hormones, notably estradiol, are central to the manner in which Alzheimer’s disease manifests in the brain. These findings underscore the necessity for research methodologies that account for gender differences, especially in the preliminary stages of scientific inquiry.

Experiments that employed female animal models yielded these critical insights.

The burden of Alzheimer’s disease is unevenly distributed between genders, with women constituting approximately two-thirds of the diagnosed cases of late-onset Alzheimer’s.

Historical studies have indicated that the disease is not only more prevalent among women but also tends to be more aggressive, with women exhibiting a more rapid deterioration in cognitive functions such as memory, attention, and decision-making capabilities in contrast to men suffering from the disease.

The biological underpinnings that account for these disparities in the impact of Alzheimer’s disease between men and women remain poorly understood. Comprehending these differences is crucial for the development of effective therapeutic interventions.

Implications of Female Sex Hormones

Researchers at Western University have disclosed through a recent study involving both mice and human subjects that female sex hormones significantly influence Alzheimer’s pathology in the brain.

This study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, also accentuates the need for therapeutic strategies that focus on hormonal interconnections. Furthermore, it highlights the importance of a nuanced understanding of estradiol, a variant of the female sex hormone estrogen frequently employed in the treatment of symptoms related to menopause, within the context of Alzheimer’s disease.

Notably, the research methodology employed is as crucial as the findings themselves, indicating a shift in scientific paradigms is imperative.

Vania Prado, a professor at the Schulich School of Medicine & Dentistry and a scientist at Robarts Research Institute, states, “To comprehend the influence of sex hormones on Alzheimer’s pathology, research must adopt appropriate animal models. Regrettably, predominant research still predominantly focuses on the male brain. Our work accentuates the necessity of using animal models that, for example, emulate postmenopausal women.”

The research was spearheaded by graduate student Liliana German-Castelan, under the supervision of Vania Prado.

Neurochemical Mechanisms and Alzheimer’s Disease

A hallmark of Alzheimer’s disease is the toxic accumulation of beta-amyloid protein in the brain, which eventually impairs neural communication and cognitive functioning.

This study reveals distinct mechanisms in the male and female brains concerning the regulation of beta-amyloid protein in Alzheimer’s, with estradiol being a contributing factor.

Previous research has identified that cholinergic neurons, brain cells that produce the neurotransmitter acetylcholine, are highly susceptible to the toxic accumulation of beta-amyloid. Moreover, acetylcholine is critical for standard memory and cognitive processes.

Beta-amyloid accumulation adversely affects acetylcholine production, which in turn exacerbates Alzheimer’s pathology, thus forming a detrimental cycle.

Researchers from Western University examined this interplay between neurochemical changes and beta-amyloid buildup in Alzheimer’s-affected brains.

The Imperative for Gender-specific Research

The study revealed gender-based differences in beta-amyloid accumulation in mice upon altering levels of cholinergic activity. It also included analysis of MRI brain scans of elderly humans, analyzed separately for men and women, which is contrary to most human studies that pool male and female data.

Differences observed between male and female mice and human subjects were attributed, among other factors, to the hormonal stage of the female mice in comparison to the post-menopausal status of the female human subjects.

Additional layers of investigation were introduced into the mouse models to explore how the presence or absence of sex hormones might affect the relationship between cholinergic signaling and beta-amyloid accumulation.

Liliana German-Castelan concluded, “In the presence of estradiol, the link between acetylcholine and toxic amyloid was dissolved. However, when sex hormones were removed in female mice, the relationship mirrored the outcomes observed in human studies.”

Researchers stress that the study’s insights would have been incomplete without the inclusion of female subjects, urging for more nuanced, gender-specific approaches in future Alzheimer’s research.

Reference: The study, titled “Sex-dependent cholinergic effects on amyloid pathology: A translational study,” was published on 17 October 2023 in Alzheimer’s & Dementia. Contributing authors also include Western researchers Lisa M. Saksida and Timothy J. Bussey, along with Takashi Saito and Takaomi C. Saido from RIKEN Center for Brain Science, Japan.

Frequently Asked Questions (FAQs) about Alzheimer’s and Sex Hormones

More about Alzheimer’s and Sex Hormones

• Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
• Western University’s Schulich School of Medicine & Dentistry
• Robarts Research Institute
• RIKEN Center for Brain Science, Japan
• Canada Research Chair in Neurochemistry of Dementia
• The Role of Estradiol in Cognitive Function
• Gender Differences in Alzheimer’s Disease
• Cholinergic System and Alzheimer’s
• Beta-Amyloid and Alzheimer’s Disease