Cancer-Linked Mutations in Microglia May Drive Alzheimer’s Disease

Microglia—the brain’s resident immune cells— accumulate mutations in cancer-driving genes as we age. Instead of manifesting as cancer, these mutations may drive Alzheimer's disease (AD).

All cells accumulate somatic mutations over time. Somatic mutations in genes that regulate cell proliferation and fitness can lead to clonal expansion, a major cause of cancer. Clonal hematopoiesis, or expansion in blood cells, increases in prevalence with age and is associated with blood cancers.

Cancer-driving gene variants are enriched in Alzheimer’s brains

In the new study, researchers assessed whether somatic cancer driver variants in the brain are associated with AD. They sequenced 149 cancer-driving genes in prefrontal cortex samples from 190 AD patients and 121 age-matched healthy controls. 

In both AD and healthy samples, the researchers observed that the number of somatic variants increased with age. In the samples from AD patients, the cancer-driving genes had significantly more somatic single-nucleotide polymorphisms (sSNVs).

Cancer driver genes can be divided into two categories: oncogenes, which promote cell proliferation when activated, and tumor suppressor genes, which permit proliferation when inactivated. The researchers found a greater burden of sSNVs in tumor suppressor genes and identified five genes that commonly amassed the most mutations—TET2, ASXL1, KMT2D, ATRX, and CBL.

The researchers also confirmed that genes associated with clonal hematopoiesis harbored more mutations in AD samples and identified a significant positive association between these variants and AD risk after controlling for confounding factors such as age, sex, and APOE4 genotype.

Microglia play a key role in Alzheimer’s disease

AD is characterized by neuroinflammation, mediated by abnormally reactive microglia, and a buildup of toxic tau and amyloid protein aggregates.

During aging and neurodegeneration, the blood–brain barrier weakens, enabling monocytes to infiltrate the brain, where they differentiate into microglia-like cells. These cells are transcriptionally and functionally indistinguishable from resident microglia. The researchers hypothesized that microglia and microglia-like cells in Alzheimer’s brains may carry mutations in cancer-driving genes.

Compared to other brain cell types, microglia and microglia-like cells had more variants in genes implicated in clonal hematopoiesis as well as in cancer-driving genes. Epigenetic and transcriptomic analyses of cells harboring these variants revealed proliferative and pro-inflammatory signatures previously associated with neurodegeneration.

“We found that to some extent, Alzheimer’s disease is a little like cancer—driven by the same mutations that drive blood cancers like lymphoma and leukemia,” said Dr. Christopher Walsh, who led the team behind the new research. 

A new mechanism for Alzheimer's disease pathogenesis

As the cancer- and clonal hematopoiesis-associated mutations in the microglia and microglia-like cells in AD are linked to blood cancers, the team sequenced blood samples from people with AD. The blood cells were found to carry the same cancer mutations.

“It was actually a really unexpected finding that suggests a totally new mechanism for Alzheimer’s disease pathogenesis,” said Dr. Yue (August) Huang, a collaborator on the new research. “The findings mean that the blood’s immune cells with cancer mutations are likely getting into the brain and contributing to disease.”

The researchers propose that as proteins aggregate during AD development, microglia are triggered to proliferate and clear the waste. The microglia-like cells that stem from peripheral monocytes and carry cancer-linked mutations have a selective fitness advantage, so they are likely to clonally expand and dominate. 

However, the same selective advantage promotes inflammation, creating a more hostile environment that puts strain on surrounding neurons, contributing to neuron loss and the pathogenesis of AD.

Opening therapeutic and diagnostic avenues for Alzheimer’s disease

The identified mutations to cancer-linked genes could offer a way to screen individuals and identify whether they are at high risk for developing Alzheimer's.

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“Because it’s hard to access brain tissue in a living patient, genetic screens using blood samples could be developed to test whether a person carries these mutations, and has an increased risk of developing Alzheimer’s disease,” said Dr. Eunjung (Alice) Lee, who also contributed to the work. 

By identifying the potential role of somatic cancer driver mutations in AD pathogenesis, this research opens avenues for drug discovery that complement efforts focused on amyloid and tau.

“We have a lot of drugs to fight cancer, and some of them might be useful therapeutically for Alzheimer’s disease,” said Walsh.

Of particular interest are drugs targeting the genes found to be frequently mutated in pathogenic microglia and microglial-like cells: TET2, ASXL1, KMT2D, ATRX, and CBL. 

Targeting these genes may suppress the expansion of pathogenic microglia and, therefore, slow neurodegeneration.

Reference: Huang AY, Zhou Z, Talukdar M, et al. Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states. Cell. 2026. doi: 10.1016/j.cell.2026.03.040

This article is a rework of a press release issued by Boston Children's Hospital. Material has been edited for length and content.