Being a woman is correlated to being twice as men to develop Alzheimer's disease, but lacking a scientific foundation for why, epidemiology is limited to noting it on a population level and moving on.

A new paper seeks to create a biological hypothesis. The authors say the C/EBPβ/AEP pathway is the core factor driving the pathogenesis of neurodegenerative diseases and searched for female hormones that are dramatically changed during menopause and tested which hormone selectively activates the C/EBPβ/AEP pathway. They have identified follicle-stimulating hormone (FSH) as the major pathogenic factor.

The big limitation is the same as epidemiology. Since the work was only in mice, it is exploratory and a lot more work needs to be done to create human relevance.

"During menopause, the serum concentration of FSH strongly increases, binding to the cognate FSH receptor on neurons and activating the C/EBPβ/AEP pathway. This results in Aβ and Tau pathologies, leading to the development of AD," said Dr. Zaidi Mone, co-corresponding author of the study and professor at the Mount Sinai School of Medicine in New York.

The researchers employed different methods to demonstrate this finding. Using ovariectomized mice, they used anti-FSH antibody treatment to block FSH and inactivate the C/EBPβ/AEP pathway. They also deleted FSH receptor (FSHR) expression in neurons to abolish the binding of FSH to FSHR in the hippocampus. Both of these methods alleviated pathology and cognitive dysfunction. In addition, knockdown of C/EBPβ in the AD mice model decreased AD pathologies.

Besides working with female mice, the researchers also injected FSH into male mice and discovered that FSH promoted AD pathologies. All these findings suggest that increased FSH after menopause binds to FSHR in neurons and activates the C/EBPβ/AEP pathway, which plays an important role in triggering AD pathology.

In the near future, the team will focus on dissecting the relationship between specific risk genes such as ApoE4 and FSH to explore why female ApoE4 carriers are more vulnerable to developing AD.