Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancer, atherosclerotic cardiovascular disease, and death. CHIP-associated mutations also affect myeloid cell function. As functional alterations to microglia, the resident myeloid cells in the brain, are a key driver of Alzheimer’s disease, Bouzid, Belk et al. investigated whether CHIP affects Alzheimer’s disease risk.

Using patient data from the Framingham Heart Study (FHS) and the Cardiovascular Health Study (CHS) (n = 3,180; 258 developed incident Alzheimer’s disease dementia), the authors found that CHIP was associated with a decreased incidence of Alzheimer’s disease. They then analysed data from the Alzheimer’s Disease Sequencing Project (ADSP), and found that in patients with the APOE ε3ε3 genotype, a known risk factor for the disease, CHIP was again associated with a lower risk of Alzheimer’s-related dementia.

Mendelian randomization analysis also identified an association between CHIP and lower risk of Alzheimer’s disease, while also excluding reverse causation (that having Alzheimer’s disease causally reduces the risk of CHIP). Autopsy data revealed lower neuritic plaque density scores in the presence of CHIP, and a positive correlation between the percentage of mutant circulating cells and mutant microglia. The authors also showed considerable brain infiltration by marrow-derived mutant cells that adopted a microglial-like phenotype, a phenomenon that has not previously been described. The surprising protective role of CHIP in the context of Alzheimer’s disease adds a new level of complexity to the relationship between CHIP and common aging diseases.

Original reference: Nat. Med. https://doi.org/10.1038/s41591-023-02397-2 (2023)