There was continuous investigation into the possible link between sex hormones and Alzheimer’s disease. Several studies have suggested that the reduction of specific sex hormones, such as estrogen in women and testosterone in men, may be linked to an increased risk of Alzheimer’s disease.
Female sex hormones, according to research, play a crucial impact in how Alzheimer’s appears in the brain. The study also emphasizes the significance of creating therapeutic techniques that target these hormonal linkages. The findings suggest that more research is needed to better understand the role of estradiol – a type of the female sex hormone estrogen used therapeutically to alleviate menopausal symptoms – in Alzheimer’s disease.
Women are disproportionately affected by Alzheimer’s disease, accounting for almost two-thirds of individuals diagnosed with the late-onset form of the disease. Previous study has revealed that Alzheimer’s disease is also more severe and advances faster in women, and women with Alzheimer’s face a steeper cognitive decline (loss of memory, attention, and the capacity to communicate and make decisions) than males with the disease.
The scientific underpinnings of these discrepancies between men and women with Alzheimer’s disease remain unknown. Understanding them, on the other hand, is required for creating effective therapies. Western University researchers discovered that female sex hormones play a crucial impact in how Alzheimer’s disease appears in the brain in a recent study in mice and humans.
To understand how sex hormones play a role in Alzheimer’s, we need to study appropriate animal models. Unfortunately, most studies at this level still focus mainly on the male brain. Our research emphasizes the importance of using animal models that reflect, for instance, postmenopausal women, to understand how sex hormones influence Alzheimer’s pathology.
Vania Prado
The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, also highlights the importance of developing therapeutic strategies focused on these hormonal connections. The research indicates a need to better understand the role of estradiol – a form of the female sex hormone estrogen, used therapeutically to mitigate menopause symptoms – in Alzheimer’s disease.
While the significance of the findings is paramount, the methodology behind them is equally critical, pointing to a necessary shift in scientific approaches.
“To understand how sex hormones play a role in Alzheimer’s, we need to study appropriate animal models. Unfortunately, most studies at this level still focus mainly on the male brain. Our research emphasizes the importance of using animal models that reflect, for instance, postmenopausal women, to understand how sex hormones influence Alzheimer’s pathology,” said Vania Prado, professor, of departments of physiology and Pharmacology and Anatomy & Cell Biology at Schulich School of Medicine & Dentistry and scientist at Robarts Research Institute.
This study was led by graduate student Liliana German-Castelan, under the supervision of Vania Prado.
Alzheimer’s and the communication system of the brain
The toxic buildup of the protein beta-amyloid in the brain is one of the primary hallmarks of Alzheimer’s disease, which eventually destroys the brain’s communications system and impairs cognition. The new research demonstrates that the brain chemistry of male and female mice regulates beta-amyloid protein in Alzheimer’s disease in various ways, with the hormone estradiol playing a role in this variance.
Previous research on mice and at-risk older people has shown that cholinergic neurons, which produce the chemical messenger acetylcholine, are more vulnerable to the detrimental Alzheimer’s-associated beta-amyloid deposition in the brain. Furthermore, acetylcholine has been proven to be necessary for normal memory and cognition.
While beta-amyloid accumulation affects acetylcholine production, the subsequent loss of this chemical messenger worsens Alzheimer’s disease, producing a vicious cycle. This relationship between alterations in brain chemistry and the beta-amyloid protein buildup seen in Alzheimer’s brains was explored by a group of Western experts.
“Because male and female brains differ in the cholinergic system, we wanted to see if gender influences this relationship between acetylcholine signaling and beta-amyloid protein buildup,” said Marco Prado, professor of physiology and pharmacology and anatomy and cell biology. Marco Prado, one of the study’s authors, is also a scientist at Robarts Research Institute and the Canada Research Chair in Neurochemistry of Dementia.
From bench to real-world: representation of sexes matters
The researchers detected changes in beta-amyloid buildup in male and female mice when the levels of cholinergic activity were changed in this investigation. They also examined brain MRI pictures of healthy older people.
Unlike most human studies, which compare MRI scans of men and women, Western professor Taylor Schmitz and graduate student Hayley Shanks examined MRI brain scans and the rate of brain atrophy in aged men and women separately.
“We observed that the relationship between the integrity of the brain region where cholinergic neurons reside and beta-amyloid accumulation was the same for men and women but was different in male and female mice,” said Marco Prado. The researchers suspected that the fact the female mice being studied were not post-menopausal, while women were, could be an attributing factor to the difference.
The lead author of the study, German-Castelan, intrigued by the sex differences, decided to introduce another layer of testing into the mouse models and with the help of Western researcher Robert Gros studied female mice who were closely modelled to represent postmenopausal women. This was done to investigate how the presence or lack of sex hormones could impact the relationship between cholinergic signalling and the beta-amyloid buildup in the brain.
“We found that when the sex hormone estradiol was present, the relationship between acetylcholine and toxic amyloid was lost, but when sex hormones were eliminated in the female mice that relationship reproduced the results seen in humans,” German-Castelan, the researcher, stated.
These findings further highlight the critical need of studying amyloid and cholinergic function in the ‘peri-menopausal’ age range of 40-50 years, which is substantially younger than the patients studied in most large-scale Alzheimer’s disease studies. Indeed, the average age of the participants in this study was closer to 70.
“Which explains why there were differences between the results of male and female mice and men and women in our initial exploration,” German-Castelan went on to say. Researchers underlined that if female mice had not been included in the study, they could have missed out on important information about Alzheimer’s and gender differences.
“Women and men respond differently to medications and have a slightly different Alzheimer’s journey.” We need to investigate animal models that can mimic different components of the voyage in order to develop more effective medicines. “Sex hormones and estradiol levels are only one of these factors,” Vania Prado explained.
