For over 30 years, researchers have focused on combating Alzheimer’s disease by targeting amyloid beta plaques—harmful protein clumps that accumulate in the brain. However, a new Northwestern Medicine study offers a promising alternative approach: boosting the brain’s immune cells to more effectively clear these plaques.
This groundbreaking research could revolutionize Alzheimer’s treatment, shifting the focus from plaque removal to enhancing the brain’s natural immune defenses.
Traditional methods, including vaccines aimed at amyloid beta, have failed due to dangerous side effects, such as brain swelling. Even current FDA-approved antibody treatments, while showing some benefit, remain controversial due to modest effectiveness, potential side effects, and high costs.
David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine and director of the Abrams Research Center on Neurogenomics, highlighted that although these drugs show some improvement, they don’t cure Alzheimer’s. “These drugs stimulate the brain’s immune cells to remove amyloid beta, but our data suggests we can enhance these treatments for better results,” Gate explained.
The study, set to be published on March 6 in Nature Medicine, uses cutting-edge technology known as spatial transcriptomics. This technique allows researchers to map gene activity within human brain tissue, a breakthrough in Alzheimer’s research. By analyzing brain tissue from individuals who participated in Alzheimer’s clinical trials, the team compared those who had received amyloid-beta immunization with those who had not.
The study revealed that when amyloid-beta treatments work, microglia—immune cells in the brain—not only clear plaques but also help restore a healthier brain environment. However, not all microglia are equally effective. Some excel at plaque removal, while others are less efficient. The research also found that microglia in treated brains adopt different states depending on the brain region and type of immunization. Genes such as TREM2 and APOE were more active in microglia following treatment, aiding in the removal of amyloid beta.
“A long-standing question in Alzheimer’s research is whether immune cells, once activated to clear amyloid, remain focused on this task,” Gate noted. “Our findings show that microglia can clear amyloid and then return to a healthy state, potentially aiding in brain recovery.”
The study offers hope that Alzheimer’s disease can be halted earlier, before tau pathology—the primary driver of cognitive decline—takes hold. Known as the amyloid cascade hypothesis, this theory likens Alzheimer’s development to a row of falling dominoes: If amyloid plaques are cleared before tau pathology begins, the disease’s progression may be halted.
Gate explained, “While removing amyloid in patients with established Alzheimer’s may help, if tau spread is already underway, it becomes a more challenging fight. Early treatment, before tau pathology sets in, may prevent the domino effect entirely.”
The research also identified specific microglial mechanisms that could limit amyloid spread in certain brain regions following amyloid-targeting drug treatment. Gate believes that by understanding the genetic makeup of immune cells that respond well to treatment, we could one day bypass drug treatments and target these specific cells directly.
Though there is currently no way to precisely target these immune cells, Gate noted that advances in targeting brain cells are steadily improving.
The study examined brain tissue from six control subjects without neurological disease, six untreated Alzheimer’s patients, and 13 patients who had been vaccinated with amyloid beta. Of the 13, seven showed significant amyloid-plaque clearance, while six had limited plaque removal. The researchers then compared the immune responses in these two groups.
Lead author Lynn van Olst emphasized the uniqueness of the study, noting, “We had the rare opportunity to analyze one of the largest post-mortem brain cohorts of Alzheimer’s patients treated with amyloid-targeting drugs, similar to those approved by the FDA. This allowed us to investigate why some individuals respond well to these treatments and clear amyloid beta more effectively.”
The study provides crucial insights into the molecular and genetic factors that drive differences in immune responses and their impact on Alzheimer’s treatment, potentially paving the way for more effective therapies in the future.
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