Summary: In a paradigm-shifting discovery, researchers have found that Alzheimer’s disease shares a surprising biological driver with blood cancers like leukemia.
The study reveals that the brain’s immune cells (microglia) accumulate specific cancer-driving mutations as they age. Rather than forming tumors, these mutant cells create a “hostile” inflammatory environment that kills neurons. This suggests that Alzheimer’s may be treatable using existing cancer drugs and detectable through simple blood tests.
Key Findings
- Repurposing Cancer Drugs: Because the same mutations drive both conditions, drugs already FDA-approved for blood cancers could potentially be repurposed to slow or stop Alzheimer’s.
- A New Diagnostic Tool: Since the mutations are present in the blood, researchers envision a genetic screen that could identify high-risk individuals years before symptoms appear.
- Somatic Mosaicism: This study is a major victory for the study of “somatic mutations”, genetic changes that happen in our bodies after we are born, rather than those we inherit from our parents.
Source: Boston Children’s Hospital
As the body ages, cells naturally accumulate dozens of genetic mutations each year. New research from Boston Children’s Hospital, published in Cell, finds that the brain’s resident immune cells, microglia, amass mutations in specific cancer-driving genes yet they don’t manifest as cancer. Instead, these mutations may help drive Alzheimer’s disease.
The research team, led by Christopher Walsh, MD, PhD, Chief of the Division of Genetics and Genomics at Boston Children’s and an Investigator of the Howard Hughes Medical Institute, and collaborators Alice Eunjung Lee, PhD, and August Yue Huang, PhD, also in the Division of Genetics and Genomics, all Professors at Harvard Medical School and Associate Members of the Broad Institute of MIT and Harvard, say their study findings may provide insights into new Alzheimer’s disease diagnostics and treatments.
“We find 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 Walsh. “This is helpful because we have a lot of drugs to fight cancer and some of them might be useful therapeutically for Alzheimer’s disease.”
For the new study, the research team sequenced 149 cancer-driving genes from tissue samples in 190 brains donated from people with Alzheimer’s disease compared to 121 healthy brains.
The Alzheimer’s samples had more single DNA letter changes than the healthy tissue with the most changes found repeatedly in the same five cancer driver genes, meaning the microglia were amassing mutations in specific genes.
Microglia function as the brain’s resident immune cells, acting as garbage collectors, eating debris and infected or dying cells. Unlike the rest of the immune system cells that circulate in the blood throughout the body, microglia don’t cross the blood brain barrier — or so experts thought.
The cancer gene mutations the researchers discovered in the microglia are commonly found in blood cancers. Because of this, the team tested blood samples from people with Alzheimer’s disease for these same mutations.
The team didn’t expect the blood to have these mutations. However, Walsh’s team found the blood cells of the same Alzheimer’s patients carried the same cancer mutations too.
“It was actually a really unexpected finding that suggests a totally new mechanism for Alzheimer’s disease pathogenesis,” said Huang. “The findings mean that the blood’s immune cells with cancer mutations are likely getting into the brain and contributing to disease.”
The researchers theorize that the blood-brain barrier weakens, either by age or injury, allowing the blood’s immune cells to cross into the brain. These new arrivals then convert into microglia-like cells. Separately, clumps of proteins accumulate in the brain, triggering microglia to proliferate and respond.
The cells most likely to dominate are those with a selective advantage, such as the microglia-like cells with the cancer mutations. However, these mutant microglia also make the environment more inflammatory and hostile than that of the healthy microglia, causing innocent bystander neurons to die off, which leads to Alzheimer’s disease.
“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 Lee.
Huang and Lee performed a follow-up study, now posted as a preprint on bioRxiv. Here, they demonstrated that cancer driver mutations observed in patient blood samples increased risk of Alzheimer’s disease independently of a well-established genetic risk factor, APOE4.
Funding: This work was done in collaboration with Icahn School of Medicine at Mount Sinai and was supported by the Howard Hughes Medical Institute, the National Institute on Aging, the NIH Common Fund through the Somatic Mosaicism Across Human Tissues (SMaHT) consortium, and Suh Kyungbae Foundation (SUHF).
Key Questions Answered:
A: Not in the traditional sense. It doesn’t form a tumor or “mass.” However, it uses the same mechanism, mutations that allow certain cells to outcompete others. In this case, the “winning” cells are toxic to the brain instead of forming a lump.
A: Not yet. This is currently a research discovery, but the authors are actively looking at developing blood-based genetic screens that could one day be used in a clinic.
A: We didn’t know the targets were the same. Now that we’ve identified specific genes like those found in leukemia, we can look at “precision medicine” to target only the mutant immune cells while leaving the healthy ones alone.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics, Alzheimer’s disease, and cancer research news
Author: Joelle Zaslow
Source: Boston Children’s Hospital
Contact: Joelle Zaslow – Boston Children’s Hospital
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states” by August Yue Huang, Zinan Zhou, Maya Talukdar, Liz Enyenihi, Michael B. Miller, Brian Chhouk, Ila Rosen, Mengyue Zheng, Minye Zhou, Averill Yang, Edward Stronge, Madel Durens, Minh Nguyen, Jaejoon Choi, Boxun Zhao, Sattar Khoshkhoo, Junho Kim, Rebecca Andersen, Zheming An, Yuchen Cheng, Javier Ganz, Levan Mekerishvili, Kyle J. Travaglini, Mariano I. Gabitto, Rebecca D. Hodge, Eitan S. Kaplan, Julia A. Belk, Dan Landau, Ed S. Lein, Philip L. De Jager, David A. Bennett, Samuele G. Marro, Eirini P. Papapetrou, Eunjung Alice Lee, and Christopher A. Walsh. Cell
DOI:10.1016/j.cell.2026.03.040
Abstract
Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH).
These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin.
Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia.
These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2, ASXL1, and DNMT3A variants.
These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.
