Clonal hematopoiesis ‘surprisingly’ linked to lower risk for Alzheimer’s disease
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Clonal hematopoiesis of indeterminate potential, which has been shown to substantially increase risk for blood cancer and cardiovascular disease, also appeared associated with protection from Alzheimer’s disease, according to study results.
Siddhartha Jaiswal, MD, assistant professor of pathology at Stanford University, announced the unexpected finding during a press conference at ASH Annual Meeting and Exposition.
“Hematologic malignancies have precursor conditions,” Jaiswal said. “We identified a precursor condition for myeloid malignancies, like acute myeloid leukemia and myelodysplastic syndrome, that we termed clonal hematopoiesis of indeterminate potential, or CHIP.”
CHIP occurs when a random mutation in a set of genes affects a hematopoietic stem cell, leading to its clonal expansion, Jaiswal said. It is found in about 10% to 30% of people aged older than 70 years and may increase risk for blood cancer, as well as cause atherosclerosis and other inflammatory diseases.
Because it has no signs or symptoms, CHIP often is not detected until an individual undergoes genetic testing for conditions such as low blood count or a solid tumor.
“It is not a surprise that CHIP is associated with blood cancers ... however, we knew that the hematopoietic stem cells that harbored the CHIP mutations still retained the ability to differentiate into all of the cells in the blood system, including the immune cells, like lymphoid cells and myeloid cells as well as platelets and red blood cells,” he said.
Microglia — the resident myeloid cells in the brain — have been implicated in genome-wide association studies as key players in Alzheimer’s disease biology. In addition, a variant of the APOE gene has been shown to impact risk for late-onset disease.
Jaiswal and colleagues sought to identify potential associations of CHIP with Alzheimer’s disease dementia or neuropathologic change and determine whether the brains of CHIP carriers contained mutant marrow-derived cells.
The researchers derived data from the Trans-omics for Precision Medicine (TOPMed) project and Alzheimer’s Disease Sequencing Project (ADSP) on 5,730 people who provided blood samples for the studies. About 60% of the study participants were women, and most were aged 60 to 80 years and white.
Researchers observed a consistent association of CHIP mutations with reduced risk for Alzheimer’s disease in both the longitudinal population-based cohort study and the case-control study, as well as by examining brain pathology of people without dementia. A fixed-effects meta-analysis of results showed an approximately 35% decreased risk for Alzheimer’s disease among CHIP carriers (OR = 0.64 P = 3 x 10-5) after adjustment for age, sex and APOE genotype. The strongest protective effect of CHIP occurred among carriers of the APOE e3 or e4 alleles, whereas no such effect occurred among those with APOE e2 alleles.
CHIP presence also appeared associated with a lower burden of amyloid plaques and neurofibrillary tangles in the brains of those who did not have dementia.
Researchers then sought to determine whether the mutations in the blood of CHIP carriers also could be found in the brain by studying occipital cortex samples from autopsies of eight donors with CHIP, including six who were cognitively normal when they died.
The eight CHIP carriers had mutations in DNMT3A, TET2, ASXL1, SF3B1 and GNB1, with the highest frequency in DNMT3A and TET2, similar to the proportion in the general population. Seven of the carriers had the CHIP variants in the microglia-enriched fraction of brain, with a variant allele frequency of 0.02 to 0.28, but at low levels or absent in the other brain fractions. Single-cell assay for transposase-accessible chromatin sequencing on brain samples of two CHIP carriers and one control revealed hematopoietic cells formed a single myeloid cluster with accessible chromatin at the microglia marker genes TMEM119, P2RY12 and SALL1, but not in genes specific to monocytes or dendritic cells, according to researchers. Approximately 40% to 80% of cells in the cluster had the CHIP mutations, which suggested widespread replacement by mutant cells of the endogenous microglial pool.
“CHIP is surprisingly associated with a decreased risk for Alzheimer’s,” Jaiswal said. “The same mutations detected in blood can be found in the immune cells in the brain. We think CHIP may reduce the risk for [Alzheimer’s disease] by supplementing a failing microglial system during aging.”
The next step for research will be to determine the mechanism by which CHIP might be associated with protection from Alzheimer’s disease, Jaiswal told Healio.
“It is known that microglia are important for clearance of toxic amyloid and tau from the brain,” he said. “We hypothesize that the mutant cells are able to supplement the normal microglial activity of clearing these toxic proteins, which may become dysfunctional during aging. If true, this might suggest novel avenues for [Alzheimer’s disease] therapeutics based on mimicking the effect of the mutations.”
Perspective
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Cynthia E. Dunbar, MD
This study might give us some clues as to what happens in Alzheimer’s disease, which are sorely needed. But I would point out that having CHIP is not something that we can control, and most of the other implications of having CHIP are negative, such as having a higher risk for progressing to hematologic malignancies. More interesting and strikingly is an increased risk for heart attacks and strokes, congestive heart failure and other aspects of cardiovascular disease. I think this is why the authors expected to see, if anything, a higher rate of Alzheimer’s in patients who had clonal hematopoiesis and potentially inflammation in the brain, and they saw the converse. So, I think it sends us back to the laboratory and potentially animal models to try to find this out. But it is something you can tell a patient who finds out they have a clonal hematopoiesis mutation — it’s good. The bad news is we need to monitor you and maybe you need to stop smoking and get your diabetes under control, but the good news is, well, maybe you won’t have Alzheimer’s.
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Iberia Romina Sosa, MD, PhD
Bouzid and colleagues tested the hypothesis that CHIP mutations in microglia may be associated with Alzheimer’s disease dementia. CHIP is known to be associated with atherosclerosis risk and other inflammatory diseases, but based on data from the TOPMed project and ADSP, the authors concluded that in Alzheimer’s disease, CHIP is associated with a protective rather than a pathologic effect. The authors report no substantial differences in Alzheimer’s disease risk based on mutated driver genes; hence, it is unclear which mutations were evaluated in the TOPMed and ADSP association to lead to the CHIP protective observation, especially given the additional experiments reported.
The researchers went on to report that a causal link would be strengthened by finding known CHIP mutations in the brain, and they examined the microglia-enriched fractions of occipital cortex from eight cognitively normal autopsy donors with CHIP. To strengthen their conclusion, it would be useful if the same experiment were done in the microglia fractions of autopsy donors with Alzheimer’s disease.
Overall, the impact of CHIP in malignancy and inflammatory diseases is of great scientific interest and further exploration of these associations may have an impact on how we practice preventive medicine.
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Bouzid H, et al. Abstract 5. Presented at: ASH Annual Meeting and Exposition. Dec. 11-14, 2021; Atlanta.
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