Alzheimer’s Disease: Gene’s Role in Immune Cell Function Explored

A gene linked to Alzheimer’s disease, CASS4, is found to affect how well the brain’s immune cells control harmful protein accumulation. This discovery may offer a new therapeutic target for slowing the condition, as indicated by a recent mouse study.

John Lukens, who directs the University of Virginia’s Harrison Family Translational Research Center in Alzheimer’s and Neurodegenerative Diseases, explained to Newsweek that while CASS4 was recognized as a significant Alzheimer’s risk factor, its broader effect on brain health was less understood. “Our work reveals that CASS4 aids in microglia’s ability to manage neurotoxic amyloid beta aggregates. Its deletion worsens amyloid plaque spread, neuron damage, and cognitive decline,” Lukens noted.

The Brain’s Cleanup System

Alzheimer’s is associated with sticky amyloid-beta plaques in the brain and twisted tau protein tangles. Research highlights microglia’s role in responding to this damage. When functional, microglia can encircle amyloid-beta plaques, limiting damage.

The research team, led by Lukens, delved into CASS4 after it was pinpointed as an Alzheimer’s risk factor. Their findings suggest it helps regulate microglia in tackling harmful plaques. In mice lacking CASS4, microglia became ineffective, leading to widespread plaque spread, neuron damage, and rapid cognitive decline.

The absence of CASS4 also altered gene activity, suggesting potential implications for neurodegenerative diseases such as Parkinson’s.

Addie Walsh, the study’s lead author, stated, “These key findings offer new insights into how this lesser-studied Alzheimer’s risk gene functions, hinting at CASS4’s role in aiding microglia’s response to amyloid pathology.”

A Possible Treatment Target

Researchers believe enhancing CASS4 activity in microglia could potentially slow Alzheimer’s progression. “This suggests therapies enhancing CASS4 function in microglia might limit Alzheimer’s progression,” Lukens remarked.

Lukens’ team is also exploring CASS4’s involvement in diseases such as Parkinson’s, ALS, and multiple sclerosis. They aim to collaborate with UVA’s Manning Institute to develop CASS4-targeted drugs for potential clinical trials.

Nonetheless, independent experts advise caution. Dr. James Bateman, a behavioral neurologist, emphasized to Newsweek, “Experimental CASS4 knockout in mice leads to a cascade of biological changes causing faulty microglia and impaired amyloid clearance. Preclinical findings are crucial but not definitive. The number of promising preclinical results often outweighs successful therapy developments.” He added that while new therapies could arise, the path from discovery to application is extensive.

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. For inquiries, contact Newsweek editors Kara Dolman and Paul Donnelley.