Alzheimer’s Disease: how does the female brain differ from the male brain?
Have you ever wondered if there are differences between male and female brains? Do men and women respond differently to diseases? If you have pondered these questions, you are not alone. For example, the female brain matures earlier than the male brain. Women also experience higher prevalence of mood and anxiety disorders than men. Despite these differences, researchers in the past have mainly focused on using male animals or recruiting male participants in their studies. Two major reasons could explain this limitation. First, many results from female studies seem to be mixed and inconsistent, which makes it difficult to identify a clear trend or pattern. Second, additional factors such as the cyclical nature of female sex hormones make data interpretation more challenging. Nevertheless, it is important to understand the female body and develop treatments suitable for each sex, which could improve treatment outcomes for both male and female patients. Recently, there has been an upward trend in the number of studies dedicated towards sex differences in health and disease.
Among these differences is the prevalence of Alzheimer's Disease, which is a progressive neurodegenerative disease that involves decline in memory, thinking, learning and social skills. Approximately 66% of Alzheimer’s Disease patients are women, and women are twice as likely to develop this disease compared to men. It is also more common in women after menopause, which is around the age of 50. Alzheimer’s Disease patients often experience a loss of acetylcholine, which is a neurotransmitter that carries messages between nerve cells and is involved in memory, attention and arousal. In particular, this loss of acetylcholine often occurs in the basal forebrain, which is a brain region also responsible for attention, memory and sleep-wake control. Furthermore, neurotoxic, sticky protein aggregates known as amyloid-beta, tend to clump together around neurons and disrupt their normal functioning. Imagine you have some gum pieces stuck in an old engine that has accumulated many mileage. No matter how hard you try to start the engine, these sticky gum pieces will make it difficult for the engine to run smoothly, just like how amyloid-beta pieces will prevent neurons from sending signals to other neurons. Over time, it could trigger inflammation locally and lead to cell death. Although extensive studies have been conducted on Alzheimer’s Disease previously, it is still unclear how biological sex plays a role in disease progression – specifically, how female sex hormones affect the levels of acetylcholine and amyloid-beta in the brain.
To answer this research question, German-Castelan and colleagues (2023) at Western University used a rodent model to investigate the relationship between acetylcholine and amyloid-beta levels in male and female brains. Particularly, they utilized genetically modified mice to model Alzheimer’s Disease in human. Previous studies had shown that this mouse model displayed amyloid-beta accumulation in the brain and memory impairments, which are symptoms of Alzheimer’s Disease in human population. In the current study, German-Castelan and colleagues (2023) indirectly increased acetylcholine levels in the brain by changing the levels of vesicular acetylcholine transporter (VAChT), to observe how it affects amyloid-beta levels in brain regions normally affected by Alzheimer’s disease. Interestingly, they found that male mice with higher VAChT (acetylcholine) levels had less amyloid-beta in the brain compared to the male control group – male mice with regular VAChT (acetylcholine) levels. However, female mice with higher VAChT (acetylcholine) levels did not differ significantly from the female control group, in terms of amyloid-beta levels. These results showed an interesting difference in how the male and female brains regulate amyloid-beta levels. Since higher VAChT (acetylcholine) levels decreased the amount of neurotoxic amyloid-beta in the male brain, it suggested that treatments involving increasing acetylcholine levels might work better in male Alzheimer’s Disease patients but not female patients.
Next, German-Castelan and colleagues (2023) examined whether female sex hormones affect the relationship between acetylcholine and amyloid-beta. They conducted ovariectomy on female mice, which is a procedure of removing the ovaries to deplete female sex hormones in the body. This could also model the hormonal state of post-menopausal women. Surprisingly, when they repeated the same experiment, they found that ovariectomized female mice with high VAChT (acetylcholine) levels actually had less amyloid beta in cortical regions compared to the control group – ovariectomized female mice with normal VAChT (acetylcholine) levels. This was similar to the findings in male mice! These new results indicated that female sex hormones disrupt acetylcholine’s regulation on amyloid-beta levels in the brain, which could be relevant to post-menopausal Alzheimer’s Disease patients concurrently receiving hormone replacement therapy and treatments that increase acetylcholine levels in the brain.
To summarize, this study demonstrated sex differences in an Alzheimer’s Disease mouse model. The regulation of amyloid-beta levels by acetylcholine is sex-dependent, where higher VAChT (acetylcholine) levels decreases amyloid-beta accumulation in males only. Interestingly, in females with low circulating sex hormones, high VAChT (acetylcholine) levels similarly reduces amyloid-beta levels and seems to have protective effects. Overall, this study is relevant to post-menopausal women receiving treatments for Alzheimer’s Disease, especially those who are taking cholinesterase inhibitors (ChEIs). ChEIs are drugs commonly prescribed for Alzheimer’s Disease patients to increase brain acetylcholine levels. For post-menopausal Alzheimer’s Disease patients, concurrently receiving hormone replacement therapy could hinder the beneficial effects of ChEIs treatment, which is a factor to consider before taking both treatments.
Although there are anatomical differences between mouse and human, this study still serves as an important first step to better understand how male and female brains differ during Alzheimer’s Disease progression. Future studies can investigate sex differences in other aspects of the disease, such as cognitive or behavioural outcomes, genetic and psychosocial factors, which helps advance the development of sex-specific treatments and significantly improve treatment outcomes for Alzheimer’s Disease patients.
Original Article: German-Castelan, L., Shanks, H. R. C., Gros, R., Saito, T., Saido, T. C., Saksida, L. M., Bussey, T. J., Prado, M. A. M., Schmitz, T. W., Prado, V. F., & Australian Imaging Biomarkers and Lifestyle flagship study of ageing. (2024). Sex-dependent cholinergic effects on amyloid pathology: A translational study. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 20(2), 995–1012. https://doi.org/10.1002/alz.13481