“CHIP has been associated with haematologic malignancies, atherosclerosis, and increased mortality,” explained Dr Hind Bouzid (Stanford University, CA, USA). The current study investigated the relation between CHIP and neurodegenerative disease via a longitudinal cohort study, a case-control study, a mendelian randomisation, and brain pathology assessment.
The longitudinal cohort study included 3,180 patients, including 258 patients with confirmed AD, and assessed the relation of AD and CHIP. The analysis demonstrated that CHIP carriers had a reduced risk of AD compared with non-carriers (sub-distribution HR 0.62; P=0.021). This unexpected association was subsequently assessed in a case-control study, including 1,104 patients with confirmed AD and 1,446 control participants. CHIP carriers were linked to a reduced risk of AD (OR 0.66; P<0.001), confirming the results of the longitudinal cohort study.
Next, a Mendelian randomisation was performed to evaluate the relation between the genetic causality of CHIP and the risk of AD. Three independent loci for risk of CHIP from a prior CHIP genetic association study (GAS) were used as variables for CHIP exposure2. This analysis found that an increased genetic risk of developing CHIP was linked to a reduced risk of AD (OR 0.92; P=0.006). Notably, the association of CHIP and a reduced risk of AD was observed in individuals with APOE ε3 or ε4 alleles, but not in individuals with APOE ε2 alleles.
Hereafter, Dr Bouzid conducted a brain pathology study to assess whether CHIP influenced AD pathologic features. It was found that CHIP carriers displayed lower levels of amyloid and tau pathology, assessed via CERAD scores (OR 0.50; P=0.003) and Braak scores (OR 0.56; P=0.015), respectively. Dr Bouzid also found that mutant haematopoietic stem cells infiltrate the brain of CHIP carriers and resemble microglial tissue. Furthermore, these mutant cells replaced endogenous microglia in the ageing brain, suggesting a support function of CHIP in the failing microglial system of older individuals.
1. Bouzid H. Clonal hematopoiesis is associated with reduced risk of Alzheimer’s disease. PSS, ASH 2021 Scientific Sessions, 11–14 December.
2. Bick AG, et al. Nature. 2020;586:763-768