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Researchers have demonstrated an unexpected association between the presence of clonal hematopoiesis of indeterminate potential (CHIP) and protection from Alzheimer’s disease (AD) dementia. The findings were presented by Hind Bouzid, PhD, of Stanford University School of Medicine in Palo Alto, California, at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Clonal hematopoiesis of indeterminate potential is a condition in which a hematopoietic stem cell incurs a somatic mutation that confers a selective advantage to that cell,” explained Dr Jennifer Trowbridge, of the Jackson Laboratory, who introduced Dr Bouzid in the Plenary Scientific Session. “Thusfar, individuals with CHIP have been found to have increased risk of hematologic malignancies, atherosclerosis, and increased all-cause mortality.”

To test for an association between CHIP and AD, Dr Bouzid and colleagues used data from the Trans-omics for Precision Medicine project (TOPMed; a longitudinal cohort study unselected for Alzheimer’s disease) and the Alzheimer’s Disease Sequencing Project (ADSP; case-control study), which have whole genome or exome sequencing data and Alzheimer’s disease phenotype data from 5730 individuals.

A fixed-effects meta-analysis of the TOPMed data (Cardiovascular Health Study, 166/743 [22.3%] incident AD) and Framingham Heart Study, 92/2437 [3.8%] incident AD) indicated an association between CHIP and reduced hazard of incident AD (subdistribution hazard ratio [SHR], 0.62; 95% CI, 0.42-0.93; P =.021).

The team confirmed this finding in the ADSP population (1140 AD case participants and 1446 dementia-free control participants), wherein CHIP was associated with reduced risk of prevalent AD (odds ratio [OR], 0.66; 95% CI, 0.53-0.84; P =5.1 x 10-4; adjusted for age, sex and APOE genotype).

They then selected 3 independent variants that reached genome-wide significance in a CHIP genetic association study as variables for CHIP exposure and used summary statistics from a large AD genome-wide association study to conduct a third confirmation study. Increased genetic risk of developing CHIP was also associated with reduced risk of AD (OR, 0.92; 95% CI, 0.86-0.98; P=5.6 x 10-3).

To begin to draw a causal link, the investigators evaluated associations of CHIP with AD brain pathology as well. Using ADSP data in over 400 individuals, they demonstrated that the presence of CHIP was associated with a reduced burden of amyloid plaques (OR, 0.50; 95% CI, 0.31-0.79; P =3.2 x 10-3) and neurofibrillary tangles (OR, 0.56; 95% CI, 0.35-0.89; P =.015) in the brains of those without dementia.

They also assessed whether the protective effect of CHIP was influenced by the APOE genotype, the dominant genetic risk factor for AD. The protective effect of CHIP was strongest in individuals with APOE e3 (HR, 0.53; 95% CI, 0.29-0.96; P =.036) or e4 (HR, 0.51; 95% CI, 0.26-1.42; P =.25) alleles but was not observed in those with the APOE e2 allele (HR, 1.55; 95% CI, 0.59-4.34; P =.36). 

“The likelihood of a causal link between CHIP and AD would be strengthened if bone-marrow derived CHIP cells could be [found] in infiltrating the aging brain,” said Dr Bouzid.  

To determine if the mutations in the blood of individuals with CHIP could also be found in the brain, they obtained donor occipital cortex samples from 8 individuals with CHIP and 1 donor without CHIP (age 80 years and greater) during autopsy. At the time of death, 6 of these individuals were cognitively normal. Detailed genetic analyses revealed that the 8 individuals with CHIP had mutations in DNMT3A, TET2, ASXL1, SF3B1, and GNB1. The investigators found that the CHIP somatic variants were present in the microglia enriched (NeuN- c-Maf+) fraction of brain in 7 of the 8 individuals with CHIP.

The team conducted single-cell sequencing to determine chromatin accessibility in the brain samples from 2 individuals with CHIP and 1 control individual. They found that hematopoietic cells in the 3 samples formed a single myeloid cluster, and the chromatin was accessible at microglia marker genes, TMEM119, P2RY12, and SALL1. The proportion of these cells ranged from about 40% to 80% across brain samples from the individuals with CHIP.

“These mutated cells are indistinguishable from microglia and comprise a large fraction of the microglial pool,” concluded Dr Bouzid. “We hypothesize that chip may reduce the risk of AD by supplementing a failing microglial system during aging, for example, by enhancing the ability of these cells to remove toxic amyloid aggregates.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Bouzid H, Belk J, Jan M, et al. Clonal hematopoiesis is associated with reduced risk of Alzheimer’s disease. Presented at ASH 2021; December 11 to 14, 2021. Abstract 5.

This article originally appeared on Hematology Advisor