The lab made important findings using female animal models. Female sex hormones, especially estradiol, play a key role in how Alzheimer's manifests in the brain, new research shows, underscoring the need for gender-specific approaches and early research. Alzheimer's disease disproportionately affects women, accounting for approximately two-thirds of those diagnosed with late-onset Alzheimer's disease.
Previous research has shown that Alzheimer's disease occurs more frequently and progresses more quickly in women, with cognitive abilities (memory, attention, and communication and decision-making skills) declining more quickly in female Alzheimer's patients than in male patients.
The biological basis for these differences between men and women with Alzheimer's disease is not well understood. However, understanding these differences is necessary to develop appropriate therapies.
The role of female sex hormones
In a new study of mice and humans, Western University researchers have found that female sex hormones play an important role in how Alzheimer's disease manifests itself in the brain.
The study, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, also highlights the importance of developing treatment strategies that target these hormonal links. The research suggests there is a need to better understand the role of estradiol - a form of the female sex hormone estrogen that is used to relieve menopausal symptoms - in Alzheimer's disease.
While the findings are significant, the methodology behind them is equally crucial, suggesting that scientific methods must change.
"To understand how sex hormones play a role in Alzheimer's disease, we need to study appropriate animal models. Unfortunately, most research in this area still focuses mainly on the male brain. Our study highlights the importance of using animal models that reflect conditions such as postmenopausal women to understand how sex hormones influence Alzheimer's pathology," said Vania Prado, professor in the Departments of Physiology and Pharmacology and Department of Anatomy and Cell Biology at the Schulich School of Medicine and Dentistry and a scientist at the Robarts Institute.
The research was conducted by graduate student Liliana German-Castelan under the guidance of Vania Prado.
Brain communication and Alzheimer's disease
One of the main hallmarks of Alzheimer's disease is the toxic accumulation of beta-amyloid in the brain, ultimately disrupting the brain's communication systems and affecting cognition. New research shows that the brain chemistry of male and female mice regulates beta-amyloid in Alzheimer's disease differently, and that the hormone estradiol contributes to the difference.
Previous studies in mice and high-risk older adults have shown that cholinergic neurons, a type of brain cell that produces the chemical messenger acetylcholine, are particularly vulnerable to damage from Alzheimer's-related accumulation of beta-amyloid in the brain. Additionally, acetylcholine is critical for normal memory and cognitive abilities.
The aggregation of beta-amyloid affects the production of acetylcholine, and the subsequent loss of this chemical messenger further aggravates the pathological changes of Alzheimer's disease, creating a vicious cycle.
The Western research team studied the interaction between changes in brain chemistry and the accumulation of beta-amyloid protein that occurs in brains affected by Alzheimer's disease.
"Because there are differences in the cholinergic system in male and female brains, we wanted to see if gender affects the relationship between acetylcholine signaling and beta-amyloid accumulation," said Marco Prado, a professor in the Department of Physiology and Pharmacology and the Department of Anatomy and Cell Biology. One of the study's authors, Marco Prado, is also a Canada Research Chair in Neurochemistry of Dementia and a scientist at the Robarts Institute.
The importance of gender analysis
In this study, the researchers observed differences in the amount of beta-amyloid accumulated in male and female mice when changing levels of cholinergic activity. Additionally, they analyzed brain MRI images of healthy older adults.
Unlike most human studies, which analyze MRI scans of men and women together, Western University professor Taylor Schmitz and graduate student Hayley Shanks analyzed MRI brain scans and rates of brain damage separately in older men and women.
"We observed that the relationship between the integrity of brain regions where cholinergic neurons are located and beta-amyloid accumulation is the same for men and women, but different for male and female mice," Marco Prado said. "The researchers suspect that the fact that the female mice studied were not menopausal, while the women were, may be a factor in the difference."
The study's lead author, Germán Castellan, was interested in sex differences and decided to introduce another layer of testing in mouse models, and with the help of Western researcher Robert Gross, he studied female mice representative of postmenopausal women. This was done to study how the presence or absence of sex hormones affects the relationship between cholinergic signaling and beta-amyloid buildup in the brain.
"We found that the relationship between acetylcholine and toxic amyloid disappeared when the sex hormone estradiol was present, but when the sex hormone was eliminated from female mice, the relationship reproduced the results seen in humans," German-Castelan said. "These findings also indicate an urgent need to study the effects of 40-50 year olds on Amyloid and cholinergic function in menopausal age groups are much younger than in most large-scale Alzheimer's studies, and the fact that the average age of the sample in this study was close to 70 years old explains why the results were different between male and female mice and men and women in our initial exploration."
The researchers stressed that if they had not included female mice in the study, they could have missed important information about Alzheimer's disease and sex differences.
"Women and men respond differently to drugs and somewhat differently in the course of Alzheimer's disease treatment. To develop more effective treatments, we need to study animal models that can reproduce the different processes. Sex hormones and estradiol levels are just one factor," says Vania Prado.