Researchers have pinpointed a new mechanism that may explain why women with the APOE4 gene are at even greater risk for Alzheimer’s disease than are male carriers. The discovery centers on neutrophils, a type of white blood cell that normally helps the body fight off infections. In female APOE4 carriers, these neutrophils interact with microglia, the brain’s immune cells, in a way that interferes with the microglia’s ability to protect the brain. This interaction is linked to increased plaque buildup in the brain and cognitive decline. By blocking the interaction in animal models, scientists were able to restore microglial function and improve cognitive performance, offering the hope of a future treatment tailored to female APOE4 carriers.

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The APOE4 gene is recognized as the most potent genetic risk factor for sporadic Alzheimer’s disease. While it raises the risk in both sexes, women face a disproportionately higher threat. A single copy of APOE4 increases the odds that a woman will develop Alzheimer’s disease by three- to four-fold compared to a man with the same genotype. The exact mechanisms behind this heightened vulnerability have not been fully deciphered, but new evidence points to a troubling interplay between the immune systems of the body and brain. This interaction, triggered by APOE4, disables the brain’s immune cells, crippling their ability to combat the amyloid plaque buildup marking the early development of Alzheimer’s pathology.

Historically, scientists believed that the body’s peripheral immune system and the brain’s neuroimmune system operated separately. Researchers thought these systems only crossed paths when something went wrong, such as in neurodegenerative diseases, and that such interactions harmed the brain. However, ongoing research has revealed a much more complex and interconnected relationship between the two.

“We are starting to understand that the brain is not isolated, and Alzheimer’s disease is not isolated in the brain,” Dr. Oleg Butovsky explains. “It may be affected by peripheral immunity, and this is a major concept we are pursuing.”

Microglia, the brain’s immune cells, remain in a homeostatic state unless confronted by a threat and then shift into a disease-associated state known as MGnD or DAM. However, when Butovsky’s lab examined post-mortem human brain tissue, they found that in female APOE4 carriers, microglia failed to transition into their disease-fighting state in the presence of amyloid plaques. They also found neutrophils—the most abundant cells of the peripheral immune system—nearby.

To explore the relationship between neutrophils and microglia in female APOE4 carriers, the lab turned to mouse models of Alzheimer’s disease. They discovered that neutrophils expressing APOE can infiltrate the brain to interact with microglia. However, when the neutrophils express the APOE4 variant, they release a protein called IL-17F, which binds to microglia and prevents the critical transition to a disease-fighting state. As a result, microglia cannot remove amyloid beta, which leads to an increase in plaque buildup and a decline in cognitive function in the mice. Removing APOE4 from the neutrophils or blocking IL-17F restored the microglia’s protective abilities.

Dr. Neta Rosenzweig, who spearheaded the study in Butovsky’s lab, likens the two immune systems to an army. In the periphery, there are many divisions with different soldiers, each overseeing a different function. In contrast, the brain only has one immune soldier—the microglia.

“In Alzheimer’s disease,” Dr. Rosenzweig explains, “the microglia are less efficient in clearing up all the damage because they have too much to deal with. The [peripheral] immune system’s role is to help them. It is only now that we are starting to understand that we want immune cells to infiltrate the brain.” But what should be a beneficial relationship becomes toxic in female APOE4 carriers.

Blood samples from patients revealed that female APOE4 carriers with cognitive impairments had higher levels of the neutrophils that inhibit microglia.

“If immune cells are like soldiers in an army, then APOE4 neutrophils are a Trojan horse,” explains Dr. Butovsky. Under normal circumstances, neutrophils do not pose a threat to microglia and might even serve as beneficial allies, but when APOE4 is present, neutrophils switch sides and disable their immune counterparts in the brain.

Drs. Butovsky and Rosenzweig are quick to point out that starting their research with human samples was crucial. “If we always start with mice,” Dr. Butovsky notes, “we’re going to miss a lot of opportunities.” Observing the effects in human tissue first and then validating their findings in mouse models led to the discovery of this interaction between the peripheral and brain immune systems that influences Alzheimer’s risk.

This discovery also holds therapeutic potential. Women are more likely than men to develop the disease during their lifetime, and being an APOE4 carrier increases the risk further. Developing a treatment that blocks the harmful crosstalk between neutrophils and microglia in female APOE4 carriers could provide a much-needed intervention for this high-risk group.

Published in Nature Medicine

Howard L. Weiner, M.D., Brigham and Women’s Hospital/Harvard Medical School

Mathew Blurton-Jones, Ph.D., University of California, Irvine

Oleg Butovsky, Ph.D., Brigham and Women’s Hospital

Neta Rosenzweig, Ph.D., Brigham and Women’s Hospital

Sex-dependent APOE4 neutrophil–microglia interactions drive cognitive impairment in Alzheimer’s disease