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By Melissa Fleur Afshar
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A gene linked to Alzheimer's disease has been found to have vulnerabilities in effectively making sure that the brain's immune cells keep harmful protein build-up at bay. The discovery offers researchers a potential new target for slowing the condition through therapies linked to the gene, according to a recent study in mice.
John Lukens, the director of the University of Virginia’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases, told Newsweek that the gene, CASS4, had previously been identified as a major Alzheimer’s risk gene, but scientists knew relatively little about how it affected brain health at large.
“Our work shows that CASS4 helps to enable microglia to corral and contain neurotoxic amyloid beta aggregates and that its deletion leads to aggravated amyloid plaque spread, damage to neurons, and cognitive decline,” Lukens said.
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The findings are early and come from laboratory mice, meaning it remains unclear whether targeting CASS4 could produce the same effects in people, especially those already in the early stages of disease onset. But researchers say understanding how the gene interacts with microglia, the brain’s resident immune cells responsible for clearing out waste, could point toward new approaches for limiting Alzheimer’s progression.
The Brain’s Cleanup System
Alzheimer’s disease is associated with the accumulation of sticky amyloid-beta plaques in the brain, alongside twisted tangles of tau proteins. Research has increasingly implicated microglia in how the brain responds to this damage.
When working properly, microglia can form protective barriers around amyloid-beta plaques and compact them, helping to limit their potential harm in the surrounding areas.
The Virginia-based research team, led by Lukens, investigated CASS4 after numerous studies identified it as an Alzheimer’s risk factor. They found that the gene helps regulate microglia and their response to harmful plaques.
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When CASS4 was disrupted in mice, microglia became less effective at containing and compacting amyloid-beta. The plaques spread more aggressively, amyloid accumulated, neurons were damaged and the animals quickly fell into cognitive decline.
The loss of CASS4 also triggered broader changes in gene activity that researchers said may have implications for other neurodegenerative diseases like Parkinson's disease.
Addie Walsh, the first author of the study, told Newsweek: “These are important findings because they give us new insight into how this understudied Alzheimer’s disease risk gene functions in the brain and suggest that CASS4 may normally help microglia respond to amyloid pathology.”
A Possible Treatment Target
The researchers believe therapies designed to boost CASS4 activity in microglia could eventually provide another way of limiting Alzheimer’s progression.
“This work suggests that therapeutics that promote CASS4 function in microglia could provide a novel strategy to limit Alzheimer’s disease progression,” Lukens said.
His team also wants to determine whether CASS4 plays a role in Parkinson’s disease, Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, and multiple sclerosis. Lukens said the researchers are interested in working with collaborators at UVA’s Manning Institute to develop CASS4-targeting drugs that could eventually be investigated in clinical trials.
However, independent experts cautioned that evidence from mice is only an initial step toward a possible treatment.
“When this gene, CASS4, is experimentally knocked out in mice, it results in a cascade of biological changes resulting in faulty microglia and impaired amyloid plaque clearance,” behavioral neurologist Dr. James Bateman told Newsweek. “It’s important to remember that preclinical findings are important and critical steps in developing new treatments, but the number of promising findings in pre-clinical models far outweighs successful development of therapies.
“This may result in new therapies, but there’s a long pathway between these important findings and that possible eventuality," the Alzheimer's expert added.
Reference
Lukens, J. R., Walsh, A. E. et al. (2026). Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20260104.
Contact Newsweek editors on this story: Kara Dolman and Paul Donnelley.
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