Endeavor Health researchers find brain waste buildup from gene mutation raises Alzheimer's risk

EVANSTON, Ill., Sept. 22, 2025 /PRNewswire/ -- Researchers at Endeavor Health have discovered a gene mutation that may cause fat and waste to build up in the brain, contributing to Alzheimer's disease, a devastating degenerative condition that causes memory loss, cognitive decline and changes to behavior and personality. Their work is published in the scientific journal, Nature.

The researchers found that a mutation on the PICALM gene could make the microglia – specialized immune cells that serve as the brain's cleanup crew – less effective, leading to waste buildup and cell damage. The microglia rely on PICALM proteins to help with their cleaning efforts.

Understanding this connection could point toward new ways to treat or prevent the disease, which currently affects around 7 million Americans – and the number of new cases per year is expected to double by 2060.

"To solve the problem, we first have to understand what causes it," said study lead Jubao Duan, Ph.D., Endeavor Health's Co-Director of the Center for Psychiatric Genetics, Charles R. Walgreen Research Chair and a professor at the University of Chicago. "This is a step forward in understanding how PICALM can contribute to Alzheimer's, and may point to new treatments and therapies that could help many people."

To see the effects of this mutation, the researchers made their own microglia from blood cells. Then, Dr. Duan's team, working with Dr. Gopal Thinakaran's team at University of South Florida, used a gene editing tool called CRISPR to create the mutation on the PICALM gene inside the microglia.

With the mutation, fewer PICALM proteins were made, making the microglia's cleaning efforts less effective at removing waste like fat, amyloid beta (a substance that builds up in the brains of people with Alzheimer's) and broken cell parts. Dr. Alena Kozlova, a post-doctoral fellow in Dr. Duan's lab at Endeavor Health, who is the first author of the paper, said the extra waste can cause damage to the brain cells, making Alzheimer's symptoms worse.

"It's like a snowball rolling downhill," Dr. Kozlova said. "The waste keeps building up and hurting the brain more and more."

Dr. Duan has been studying the connection between genes and brain diseases for over 20 years. He hunted for risk genes as part of the Genome-wide Association Study (GWAS), including those of schizophrenia, another devastating brain disorder. He's now working to understand what those risk genes do as part of Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene), backed by the National Institutes of Mental Health.

PICALM is a piece of the puzzle for understanding the neurodegenerative brain disorders, he said, but there's still a lot more to learn.

"This is an important step," he said. "Alzheimer's is a complex disease, with many mysteries still to solve. But I hope this finding may lead us to a better understanding on how to target this fat buildup for preventing and treating Alzheimer's disease and some other brain disorders."

CONTACT: Baylee Pulliam
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SOURCE Endeavor Health