Researchers have uncovered evidence that age-related genetic mutations commonly associated with cancer and blood disorders may also contribute to the chronic brain inflammation characteristic of Alzheimer’s disease.
In a study published in Cell, investigators from the Icahn School of Medicine at Mount Sinai and Boston Children’s Hospital identified somatic mutations in brain immune cells from patients with Alzheimer’s disease. The findings suggest that genetic alterations acquired during aging may reshape the behavior of these cells, driving inflammatory processes linked to neurodegeneration.
The work introduces a potential new biological mechanism connecting aging, immune dysfunction, and Alzheimer’s disease, a condition that affects millions of people worldwide and remains one of the leading causes of dementia.
Linking aging, immunity, and neurodegeneration
Inflammation has long been recognized as a central feature of Alzheimer’s disease. Activated immune cells are commonly observed surrounding amyloid plaques and other pathological hallmarks of the disease. However, the factors that initiate and sustain these harmful immune responses have remained incompletely understood.
The new study focused on microglia, the brain’s resident immune cells. These specialized cells play critical roles in maintaining neural health by clearing cellular debris, regulating synaptic connections, responding to injury, and coordinating immune activity within the central nervous system.
Previous research has shown that microglia can adopt disease-associated states during Alzheimer’s progression, but the molecular triggers responsible for these changes have been unclear.
“Our data suggest that some immune cells in Alzheimer’s disease undergo genetic changes over time that alter their behavior and potentially contribute to chronic inflammation in the brain,” said senior author Samuele Marro, PhD, associate professor in the Nash Family Department of Neuroscience and The Friedman Brain Institute at Mount Sinai.
“These findings provide a new framework for understanding how aging, immune dysfunction, and neurodegeneration may intersect in Alzheimer’s disease.”
Large-scale analysis of Alzheimer’s brains
To investigate whether acquired mutations might contribute to disease pathology, researchers analyzed 311 postmortem brain samples from individuals with Alzheimer’s disease and age-matched controls.
Using ultra-deep sequencing, the team screened 149 genes frequently associated with cancer and clonal hematopoiesis, an age-related condition in which blood stem cells acquire mutations that allow certain cell populations to expand disproportionately over time.
The analysis revealed significantly higher numbers of somatic mutations in Alzheimer’s disease brains compared with controls.
Several of the most frequently mutated genes, including TET2, DNMT3A, and ASXL1, are well-known drivers of clonal hematopoiesis and have previously been implicated in age-related blood disorders and cancer development.
Many of these mutations were highly enriched in microglia-like immune cells while being largely absent from neurons, suggesting that immune cells may be a primary target of these age-related genetic alterations.
Evidence for blood-derived immune cell involvement
The researchers also examined matched blood samples from some patients and found that many of the same mutations detected in the brain were present in circulating blood cells.
This observation suggests a possible route by which mutated immune cells originating from the blood may enter the brain and adopt microglia-like functions.
Growing evidence has indicated that peripheral immune cells can contribute to neuroinflammation under certain conditions. The new findings raise the possibility that age-related expansion of mutated blood cell clones could influence inflammatory processes within the brain.
Such a mechanism would provide a direct biological link between clonal hematopoiesis—an increasingly recognized consequence of aging—and neurodegenerative disease.
Functional effects of Alzheimer’s-associated mutations
To determine whether these mutations actively alter immune cell behavior, the researchers combined single-cell analyses with stem cell-based experimental models.
Using CRISPR gene editing, they engineered induced pluripotent stem cell-derived microglia-like cells carrying mutations identified in Alzheimer’s disease samples.
The resulting cells displayed profound changes in gene expression, adopting inflammatory programs and disease-associated microglial states that have previously been linked to neurodegeneration.
“Our study provides functional evidence that mutations commonly associated with aging blood cells and cancer biology can directly alter the behavior of brain immune cells,” said co-corresponding author Eirini Papapetrou, MD, PhD, professor of oncological sciences at Mount Sinai and director of the Center for Advancement of Blood Cancer Therapies.
“These mutated cells showed inflammatory signatures strongly associated with neurodegeneration.”
The findings suggest that these mutations are not merely bystanders but may actively influence cellular pathways involved in disease progression.
A potential new contributor to Alzheimer’s pathology
The study expands the growing view of Alzheimer’s disease as a disorder involving complex interactions between the immune system and the nervous system.
Historically, Alzheimer’s research has focused heavily on amyloid-beta plaques and tau tangles. More recently, attention has shifted toward the role of neuroinflammation and immune dysfunction as key drivers of disease progression.
The identification of somatic mutations in microglia-like cells adds another layer to this emerging picture. Rather than being solely inherited or environmentally driven, some aspects of Alzheimer’s pathology may arise from genetic alterations that accumulate naturally with age.
Because clonal hematopoiesis becomes increasingly common in older adults, the findings may have implications beyond Alzheimer’s disease and could influence understanding of other neurodegenerative disorders characterized by chronic inflammation.
Implications for future therapies
Although the study does not establish that these mutations directly cause Alzheimer’s disease, it identifies a plausible mechanism through which age-related genetic changes could exacerbate neurodegeneration.
Future studies will be needed to determine how early these mutations emerge, whether they predict disease risk, and whether interventions targeting mutated immune cell populations could slow disease progression.
“This work highlights a potentially important connection between aging 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 researchers are now planning follow-up studies in animal models to further investigate the role of mutated immune cells in Alzheimer’s disease and evaluate whether reducing their inflammatory activity can modify the course of neurodegeneration.
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