The finding, published in Cell, suggests that mutations commonly associated with blood cancers and clonal haematopoiesis can appear in microglia-like immune cells in Alzheimer’s-affected brains. Rather than forming tumours, these altered cells appear to adopt inflammatory and proliferative behaviour that may contribute to neuronal damage.
The work brings together researchers from Boston Children’s Hospital, Harvard Medical School, the Broad Institute of MIT and Harvard, the Icahn School of Medicine at Mount Sinai, Columbia University, Rush Alzheimer’s Disease Center and other institutions. It adds weight to a growing view that Alzheimer’s is not only a disorder of amyloid plaques and tau tangles, but also one shaped by immune dysfunction inside the ageing brain.
Researchers analysed 311 post-mortem brain samples from people with Alzheimer’s disease and age-matched controls using ultra-deep sequencing of 149 genes associated with cancer and clonal haematopoiesis. Alzheimer’s samples showed an enrichment of acquired DNA changes in cancer driver genes, especially TET2, DNMT3A and ASXL1, which are also known in age-related blood cell mutations.
The mutations were concentrated in microglia-like brain macrophages and were largely absent from neurons. Paired blood samples showed many of the same mutations, strengthening the possibility that some altered immune cells may have originated in the blood, entered the brain and acquired microglia-like functions.
Microglia normally help maintain the brain by clearing debris, responding to injury and regulating immune activity. In Alzheimer’s disease, however, these cells can become chronically activated, releasing inflammatory signals that may worsen tissue damage. The new study points to one possible trigger for that harmful shift: age-acquired mutations that give certain immune cells a survival or growth advantage.
The team used single-nucleus RNA sequencing data from 62 additional Alzheimer’s and control brains and found copy-number changes linked to clonal haematopoiesis in Alzheimer’s microglia-like cells. Multi-omic analysis indicated that mutation-carrying cells displayed inflammatory and proliferative signatures associated with disease-linked microglial states.
Laboratory experiments offered further support for the mechanism. Researchers engineered induced pluripotent stem cell-derived microglia-like cells to carry Alzheimer’s-associated variants in TET2, ASXL1 and DNMT3A. These cells adopted inflammatory gene-expression patterns similar to those observed in disease-associated microglia, suggesting that the mutations could directly alter immune-cell behaviour.
Christopher A. Walsh, chief of the Division of Genetics and Genomics at Boston Children’s Hospital and a senior author of the study, said the findings suggest Alzheimer’s disease is, to some extent, “a little like cancer”, because some of the same mutations that drive blood cancers such as lymphoma and leukaemia may also shape destructive cell behaviour in the brain. He said the link is important because medicines developed for cancer could eventually be examined for neurological use.
August Yue Huang, a lead author, described the result as unexpected, saying it suggested a new mechanism for Alzheimer’s disease pathogenesis. The central hypothesis is that ageing, vascular injury or disease-related changes may weaken the blood-brain barrier, allowing mutated immune cells from the blood to enter the brain. Once inside, these cells may behave like microglia, expand selectively and intensify inflammatory damage.
The discovery also raises the prospect of blood-based screening. Because several mutations found in the brain were also detected in blood, future genetic tests could potentially identify people carrying risk-linked clonal mutations without requiring access to brain tissue. That possibility remains exploratory, and clinical use would require validation in larger, living patient cohorts across diverse populations.
Eunjung Alice Lee, a collaborator at Boston Children’s Hospital and Harvard Medical School, said blood-based genetic screens could be developed to assess whether a person carries such mutations and faces elevated Alzheimer’s risk. A follow-up preprint has indicated that clonal haematopoiesis mutations in blood may raise Alzheimer’s risk independently of APOE ε4, the best-known inherited genetic risk factor for late-onset disease.
The findings arrive as dementia places a growing burden on health systems. Tens of millions of people live with dementia worldwide, and Alzheimer’s disease accounts for the largest share of cases. Current treatments can slow aspects of disease progression in selected patients, but they do not reverse established neurodegeneration, making new biological targets a priority for drug developers.
Scientists are cautious about overstating the result. The study shows association and plausible mechanism, not definitive proof that the mutations cause Alzheimer’s disease. The authors also note that the role of clonal haematopoiesis in Alzheimer’s biology has appeared complex, with earlier research suggesting some forms may be linked to reduced risk. The effect may depend on the specific mutation, cell type, disease stage and immune environment.
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