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Antibodies against follicular hormone (FSH) improve memory functions in Alzheimer's disease

Aging is the most important risk factor for the development of dementia. Alois Alzheimer first described a disease in 1906 that accounts for the largest proportion of all forms of dementia (70% of cases). Nearly half of those over 85 have dementia, about two-thirds of whom are women.

In women, the disease progresses more rapidly and affects more cognitive functions than in men. We previously suspected that the drop in the female sex hormone estrogen after menopause was responsible, since estrogens have a neurotrophic effect in the brain, especially in the hippocampus. This structure is particularly relevant for learning and memory, and estrogens stimulate metabolism and ensure network stability. However, estrogen replacement therapy has not yet shown clear results with regard to the memory functions of treated women. In addition to improvements, deteriorations or no effects occurred.

In a recently published paper in Nature, a research group led by Dr. Keqiang Ye and Dr. Mone Zaidi of Emory University in Atlanta (USA) has now been able to show that it is not estrogen, but rather follicle-stimulating hormone (FSH) that may play a very important role in the observed sex difference in the development of dementia. Indeed, FSH blood levels rise sharply in women around menopause (without there being evidence of estrogen deficiency yet). During this time, many women gain weight and bone mass decreases.

In the current work, mice genetically developing Alzheimer's-like disease (due to mutations in the APP, presenilin, and tau genes) were placed in artificial menopause (by removal of the ovary). In addition to the expected FSH increase, they showed the changes typical of Alzheimer's disease, such as amyloid plaques, tau fibrils, and a loss of spatial memory. Interestingly, repeated injections of antibodies that bind FSH and block its function significantly attenuated these symptoms. Even male mice, which have lower FSH levels, benefited from this treatment. Less β-amyloid was detectable in their brains as well, and more neurons survived. In contrast, additional exogenous addition of FSH enhanced Alzheimer's symptoms in male as well as female mice.

The experiments also provided evidence that FSH can cross the blood-brain barrier and bind to specific receptors on neurons. These are coupled to a specific signaling pathways, e.g. the C/EBPβ-AEP/δ-secretase pathway, through which amyloid and pathological tau are produced. After knocking out the FSH receptors in the hippocampus of menopausal mice, the changes typical of Alzheimer's disease were significantly reduced.

In conclusion, therapeutic antibodies against FSH may represent a new strategy for the prevention and treatment of Alzheimer's disease (not only in women).

Corresponding studies are underway.

A schematic representation of the pituitary gland (hypophysis) releasing FSH from the anterior lobe into the blood (yellow cells on the left) . This occurs after stimulation by release hormones (GnRH) produced in diencephalic neurons (purple) of the hypothalamus.


Xiong J, Kang SS, Wang Z, ... , Zaidi M, Ye K (2022) FSH blockade improves cognition in mice with Alzheimer’s disease. Nature 603:470-476

Image credit: iStock/Cecilie-Arcurs, iStock/7activestudio


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