Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer’s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10−5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD. MAIN: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated expansion of hematopoietic stem cells (HSCs) found in 10–30% of those older than 70 (refs. 1,2,3,4). It most commonly occurs due to truncating or loss-of-function mutations in transcriptional regulators such as DNMT3A, TET2 and ASXL1 and can be detected by sequencing of DNA from peripheral blood or bone marrow cells5. As these are also founding mutations for hematological neoplasms such as acute myeloid leukemia, it is unsurprising that CHIP associates with a higher risk of developing these cancers1,2,6,7. However, CHIP also associates with an increased risk of atherosclerotic cardiovascular disease and death8,9,10. This link is believed to be causal as mice that are deficient for Tet2 or Dnmt3a in hematopoietic cells develop more severe cardiovascular phenotypes, possibly due to altered gene expression in mutant macrophages, which favors the more rapid progression of the lesions8,11,12. Alzheimer’s disease (AD) remains a leading cause of morbidity and mortality in the elderly, but therapies that can effectively slow or halt its progression are lacking. Genome-wide association studies (GWAS) have implicated functional alterations of microglia (MG), the macrophage-like hematopoietic cells in the brain, as a major driver of AD risk13. Because CHIP-associated mutations influence the function of myeloid cells8,11,14, we tested whether CHIP was associated with the risk of AD. RESULTS: Association between CHIP and AD dementia.To test the association between CHIP and incident AD dementia, we used data from the Framingham Heart Study (FHS) and the Cardiovascular Health Study (CHS), which are two cohorts within the Trans-omics for Precision Medicine (TOPMed) project15. CHIP variants (Supplementary Table 1) were identified from blood-derived whole-genome sequencing (WGS) data as previously described9. AD dementia was diagnosed when participants met the criteria of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) for definite, probable or possible AD. After excluding those with coronary heart disease, stroke or prior dementia, there were 2,437 participants in FHS, of whom 92 developed incident AD dementia, and 743 participants in CHS, of whom 166 developed incident AD dementia (Supplementary Table 2). Participants in CHS were substantially older on average and a higher proportion was female compared to participants in FHS, which contributed to a higher rate of AD dementia in CHS compared to FHS (22.3% versus 3.8%) in the follow-up period (Supplementary Table 2). Contrary to our expectations, the presence of CHIP was associated with a lower subdistribution hazard ratio (SHR) for incident AD dementia in fully adjusted competing risks regression (CRR) models (SHR = 0.69, P = 0.13 in CHS; SHR = 0.51, P = 0.068 in FHS; SHR = 0.63, P = 0.024 in a fixed-effects meta-analysis of the two cohorts), while the effects of age, sex and APOE genotype were as expected based on prior studies (Fig. 1a). APOE genotype was strongly associated with AD dementia risk in those without CHIP age 60 years or older (P = 8.1 × 10−8 by log-rank test), but not in CHIP carriers of the same age (P = 0.42 by log-rank test) (Fig. 1b), possibly due to smaller sample size. The inclusion of MG-associated germline polymorphisms from AD GWAS did not attenuate the effect of CHIP in these models (Supplementary Table 3)
