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Study reveals link between sex hormones and Alzheimer’s disease

The burden of Alzheimer’s disease is notably higher in women, with two-thirds of late-onset cases diagnosed in this demographic. 

As research has consistently shown, not only are women more susceptible to Alzheimer’s, but its progression is also accelerated and intensified in them, leading to a steeper decline in cognitive abilities.

Female sex hormones 

Despite the observed differences between genders, the biological underpinnings that account for these variations in Alzheimer’s progression remain unclear. Yet, discerning them is essential for devising targeted treatments.

In a new study on both mice and humans, a team of researchers led by Western University offers important insights, pinpointing the pivotal role female sex hormones play in Alzheimer’s development within the brain. 

Therapeutic potential 

Published in Alzheimer’s Dementia: The Journal of the Alzheimer’s Association, the study highlights the therapeutic potential of focusing on hormonal interactions, particularly revolving around estradiol – an estrogen variant. The methodological approach adopted is as significant as the findings themselves. 

“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,” said senior author Vania Prado, a professor at the Schulich School of Medicine & Dentistry.

“Our research emphasizes the importance of using animal models that reflect, for instance, postmenopausal women, to understand how sex hormones influence Alzheimer’s pathology.”

Beta-amyloid protein

A defining characteristic of Alzheimer’s disease is the toxic accumulation of beta-amyloid protein within the brain, which disrupts neural communication and hampers cognition. 

The experts found differential regulation of beta-amyloid protein in male and female mice brains, with estradiol playing a significant role.

Focus of the study 

Earlier research has spotlighted cholinergic neurons, known to produce acetylcholine crucial for memory and cognition, as particularly susceptible to beta-amyloid accumulation’s deleterious effects. 

The interactions between brain chemistry shifts and beta-amyloid protein aggregation in Alzheimer-affected brains was the focus of the current study.

What the researchers learned 

“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,” reported co-author Marco Prado, a professor at Western University.

The research included MRI brain scans from healthy elderly humans and observations in both male and female mice, highlighting the complexity of studying Alzheimer’s disease. The scientists made a compelling finding when female mice were modeled to simulate postmenopausal women. 

“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,” said lead author Liliana German-Castelan, a graduate student at the same institution.

Study implications 

This discovery calls for further research on amyloid and cholinergic function in individuals aged 40-50, markedly younger than most Alzheimer’s study subjects.

“Women and men respond differently to medications and have a somewhat different journey in Alzheimer’s. To develop more effective therapeutics, we need to study animal models that can reproduce different aspects of the journey. Sex hormones and estradiol levels are just one of these factors,” Prado concluded.

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