Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related phenomenon, in which a somatic mutation causes the clonal expansion of a hematopoietic stem cell in an individual without evidence of hematologic malignancy. As well as a 0.5-1% risk per year of transformation to leukemia, CHIP is also associated with a pro-inflammatory state resulting from altered effector immune cell function/development. Several lines of evidence suggest microglia play an important role in Alzheimer’s disease (AD) biology, and thus a study was conducted to test for an association between AD and CHIP using whole genome or whole exome sequencing data from over 5730 individuals. Sidd Jaiswal, MD, Stanford University, Stanford, CA, discusses the findings of the investigation, which notably discovered that the presence of CHIP was associated with a reduced risk of AD (p=0.00003). The link was seen in those with APOE e3 or e4 alleles but not APOE e2. CHIP was also associated with protection against AD-related pathology, with a reduced burden of amyloid plaques and neurofibrillary tangles seen in the brain of participants without dementia. When investigating if mutation seen in the blood of CHIP carriers could be found in the brain, CHIP somatic variants were detected in the microglia-enriched fraction of brain of 7 of 8 carriers. Overall, the evidence of a protective effect of CHIP from dementia and the finding of substantial brain infiltration of marrow-derived mutant cells suggest CHIP may have a modulating effect on the underlying pathophysiology of AD. This press briefing was recorded at the American Society of Hematology (ASH) 2021 Annual Meeting and Exposition in Atlanta, GA.
