87 Quick summary: Researchers have discovered that age related genetic mutations commonly linked to cancer and blood disorders accumulate in specialised brain immune cells and may drive the chronic inflammation and neurodegeneration characteristic of Alzheimer’s disease. By utilizing advanced genetic sequencing and stem cell models, the collaborative study demonstrated that these somatic mutations alter cellular behaviour to push microglia into highly destructive inflammatory states. These major biological findings carry critical implications for public policy and healthcare practice by introducing an entirely new paradigm for precision medicine, potentially shifting clinical therapeutic strategies towards targeting mutated immune cell populations to preserve patient cognitive well-being. Scientists at Mount Sinai and Boston Children’s Hospital have discovered cancer-linked genetic mutations inside the brain’s immune cells. These specific mutations may trigger the chronic inflammation and brain cell death that drives Alzheimer’s disease. Published in Cell, the study uncovered a potential new biological mechanism linking ageing, immune dysfunction, and Alzheimer’s Disease. The disease affects millions of people worldwide and is characterised by progressive memory loss, cognitive decline, and neurodegeneration. Although inflammation is known to play a central role in the disease, the factors that trigger harmful immune responses in the brain are not fully understood. The researchers found a high concentration of ‘somatic mutations’—genetic changes picked up during a person’s lifetime rather than inherited at birth—inside the brain’s immune cells. Many of these flaws appeared in genes tied to clonal haematopoiesis, an age-related condition where mutated blood stem cells replicate aggressively. Microglia are the brain’s essential maintenance workers: they clear cellular debris, regulate brain cell connections, and defend the central nervous system against injury. While scientists already knew these immune cells malfunction and cause brain damage in Alzheimer’s patients, the exact trigger behind this destructive shift has remained a mystery until now. To investigate, the research team analysed 311 postmortem brain samples from patients with Alzheimer’s Disease and age-matched controls using ultra-deep sequencing of 149 genes commonly associated with cancer and clonal haematopoiesis. They found significantly more somatic mutations in Alzheimer’s Disease brains, particularly in the genes TET2, DNMT3A, and ASXL1. Many of the mutations were highly enriched in microglia-like brain cells and largely absent in neurons. Researchers also detected many of the same mutations in matched blood samples, suggesting that mutated blood-derived immune cells may infiltrate the brain and adopt microglia-like functions. Using ultra-deep genetic sequencing, single-cell analyses, and stem cell-based laboratory models, the researchers demonstrated that these mutations may push brain immune cells into inflammatory and proliferative states associated with Alzheimer’s Disease progression. The researchers further validated their findings using induced pluripotent stem cell-derived microglia-like cells engineered with CRISPR to carry mutations found in Alzheimer’s disease samples. Cells carrying the mutations adopted inflammatory gene expression patterns and disease-associated microglial states previously linked to neurodegeneration. “Our data suggest that some immune cells in Alzheimer’s Disease undergo genetic changes over time that alter their behaviour and potentially contribute to chronic inflammation in the brain,” says co-corresponding author Samuele Marro, PhD, a neuroscience professor at the Icahn School of Medicine at Mount Sinai. “These findings provide a new framework for understanding how ageing, immune dysfunction, and neurodegeneration may intersect in Alzheimer’s disease.” “Our study provides functional evidence that mutations commonly associated with ageing blood cells and cancer biology can directly alter the behaviour of brain immune cells,” said co-corresponding author Eirini Papapetrou, MD, Professor of Oncological Sciences at the Icahn School and Director of the Blood Cancer Therapies. “These mutated cells showed inflammatory signatures strongly associated with neurodegeneration.” The findings suggest that age-related accumulation of mutations in immune cells may represent a previously underrecognised contributor to Alzheimer’s Disease biology and could eventually inform the development of new therapeutic strategies. “This work highlights a potentially important connection between ageing blood biology and neurodegenerative disease,” said Marro. “If confirmed in future studies, these findings could open new avenues for therapies that target harmful inflammatory immune cell populations in the brain.” The authors caution that the findings do not prove that these mutations cause Alzheimer’s Disease. Rather, they identify an association and a potential mechanism that warrants further investigation. Future studies will focus on validating the findings in animal models and exploring whether targeting mutated immune cell populations could help slow neurodegeneration. Funding for the study came from the National Institutes of Health, the Alzheimer’s Association, and several philanthropic foundations. The sweeping collaborative effort brought together researchers from Mount Sinai and Boston Children’s Hospital alongside teams from Columbia University, the Broad Institute, and Weill Cornell Medicine.