Brain immune cells may drive more damage in females than males with Alzheimer’s: Study

More than seven million Americans have Alzheimer’s disease, and two-thirds of them are women, according to the Alzheimer’s Association. The O’Banion Lab at the Del Monte Institute for Neuroscience at the University of Rochester has long been studying this disease and is looking more closely at the differences between male and female brains.

“It is well documented that males and females are diagnosed with Alzheimer’s disease at different rates,” said M. Kerry O’Banion, MD, PhD, professor of Neuroscience and Neurology. “But we still do not have a great understanding of why this is the case. We can only improve any possible treatment or prevention of this disease if we know the why, when, and where these differences are occurring.”

Uncovering Clues in the Immune Cells

New research led by O’Banion and Neuroscience graduate student Lia Calcines-Rodríguez discovered that the immune cells in the brain, known as microglia, act differently in the male and female Alzheimer’s brain, and appear to cause residual harm in the female brain. As described in their recent paper in the Journal of Neuroinflammation, they discovered that in mice, when microglia respond to amyloid-β plaques-the sticky clumps of protein that accumulate in the brain in Alzheimer’s disease— female microglia express more interferon-related genes. In the body, interferons are known for their role in combating viral infections; however, the role of interferons in Alzheimer’s disease is unknown. Previous research has shown that interferon signaling can drive neuroinflammation and can damage synapses, the connections between neurons. Researchers believe that as the microglia consume the amyloid-β plaques, they may be exposed to DNA or RNA, mistake it for a virus, and this may cause the cells to release interferon, although the exact cause and function of interferon in Alzheimer’s remains unclear.

This research also found that female microglia leave behind larger and more irregular plaques, which damage more neuronal connections than those in the male brain.

“It was surprising to see that female microglia had such a strong interferon response and that these interferon-responsive microglia were taking up more amyloid-β,” said Calcines-Rodríguez, first author of the study. “Interestingly, we did not see differences in amyloid-β pathology or microglia gene expression in females at different hormonal stages of their cycle, suggesting that hormone fluctuation may not explain these differences.” She also sees potential in the interferon signaling in microglia as a possible sex-specific, personalized treatment to combat Alzheimer’s.

Brain Immune Cells May Hold the Key to Future Treatments

Microglia are an important part of the nervous system. In a healthy brain, they help maintain a stable environment. It is understood that these cells play a significant role in the pathogenesis and progression of Alzheimer’s disease. Now, researchers aim to understand whether these differences between male and female microglia could provide a path to alter the disease course, if male and female microglia are inherently different, and if interferon signaling could be a potential pharmacological target.

Reference:

Calcines-Rodríguez, L., Noyes-Martel, N., Becker, J.L. et al. Microglial interferon signaling and Aβ plaque pathology are enhanced in female 5xFAD Alzheimer’s disease mice, independent of estrous cycle stage. J Neuroinflammation (2025). https://doi.org/10.1186/s12974-025-03659-1