Alzheimer’s Study Reveals Immune Pathway Behind Women’s Higher Vulnerability and Potential New Treatment Approach

A study led by the Institute of Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University of Elche (UMH), has identified an immune system pathway, known as interferon signaling, that could explain women’s greater vulnerability to Alzheimer’s disease.

The results, published in the Journal of Neuroinflammation, open new avenues for the development of future therapeutic strategies aimed at modulating this immune response.

The Alzheimer’s disease affects approximately twice as many women as men

Although women’s longer life expectancy explains part of this difference, there is growing evidence that biological mechanisms also play a role. In this regard, researchers observed a more intense activation of interferon signaling in women with Alzheimer’s. This pathway is one of the main defense mechanisms against viral infections, but when it remains persistently activated, it can promote inflammatory processes that are harmful to the brain.

“We knew that women develop the disease more frequently, but we didn’t know what biological mechanisms could explain this difference. Our results show that the interferon response is much more activated in women with Alzheimer’s and that this excessive activation can contribute to both brain alterations and the deterioration of cognitive function,” explained José P. López-Atalaya, the researcher who led the study.

Researchers observed a more intense activation of interferon signaling in women with Alzheimer’s compared to men

Researchers analyzed post-mortem brain tissue samples from Alzheimer’s patients and found that genes associated with the interferon response were significantly more activated in women than in men , even when both groups had a similar degree of brain damage. They subsequently confirmed this pattern in an animal model of the disease, where females showed a more intense immune response, along with greater brain inflammation and alterations in markers related to neuronal damage.

The study combined transcriptomic analysis of human brain tissue with animal models and single-cell RNA sequencing techniques, which allowed the identification of microglia, the brain’s main immune cells, as an important focus of activation of this interferon response.

Although these cells play a protective role in the nervous system, their prolonged activation can promote inflammatory processes that alter neuronal function. “Our data reinforce the idea that neuroinflammation plays a central role in the progression of Alzheimer’s disease,” said Verónica López, first author of the study.

The researchers also analyzed whether the activation of interferon signaling was a consequence of Alzheimer’s disease or whether it actively participated in its progression. To do this, they used various experimental models and found that activating this immune response was sufficient to trigger alterations characteristic of the disease , such as brain inflammation and deterioration of circuits related to memory.

The authors noted that these results were obtained in animal models and that “future clinical studies will be necessary to determine whether this approach can be translated to patients.”
Furthermore, they observed that enhancing this pathway specifically in microglia exacerbated neuroinflammatory and neurodegenerative changes.

In contrast, pharmacologically blocking it by inhibiting Sting, a key protein for activating the interferon response, reduced neuroinflammation, attenuated neuropathological alterations, and improved performance on spatial memory tests in females of the experimental Alzheimer’s model.

The authors noted that these results were obtained primarily in animal models, so “future clinical studies will be necessary to determine whether this approach can be translated to patients.” Nevertheless, they considered the findings to reinforce a line of research with therapeutic potential. “These results support the idea that pharmacological modulation of interferon signaling could become a strategy to reduce neuroinflammation and preserve brain function in Alzheimer’s disease,” concluded López-Atalaya.

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First published in iSanidad. A third-party contributor translated and adapted the article from the original. In case of discrepancy, the original will prevail.

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