The presence of clonal hematopoiesis of indeterminate potential, or CHIP, increases the risk of developing a myeloid malignancy and also cardiovascular disease—which are well-established findings—but it may also protect against developing Alzheimer’s disease, according to findings reported at the Plenary Session of the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition by Hind Bouzid, PhD, of Stanford University School of Medicine.¹

At a press briefing, senior author Siddhartha Jaiswal, MD, Assistant Professor of Pathology at Stanford University, described the unexpected discovery. “We found the opposite of what we were expecting. CHIP surprisingly was associated with a decreased risk of Alzheimer’s disease and Alzheimer’s-related neuropathology,” Dr. Jaiswal said. 

Hind Bouzid, PhD

Siddhartha Jaiswal, MD

The investigators had hypothesized that CHIP would be associated with an increased risk of Alzheimer’s disease, based on mechanisms of action. Instead, the analysis of more than 5,000 individuals showed an overall 35% to 40% reduced risk. The researchers cautioned this is an association and not proof of causality.

The investigators further found the same mutations in the microglial cells within the brain, which have immune-related functions. “This was unexpected, since it’s thought that peripheral immune cells are excluded by the blood-brain barrier. We think CHIP may reduce the risk of Alzheimer’s disease by supplementing a failing microglial system during aging,” Dr. Jaiswal told journalists.

ASH Past President Martin Tallman, MD, Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center, called the study “a fascinating abstract with lots of implications.” However, he emphasized the data are “suggestive” only, and larger studies are needed to show a clear connection.

The Rationale

CHIP mutations are acquired over time, and by age 70, they are seen in 10% to 30% of the population. Individuals found to have CHIP mutations have about a 1% per-year chance of developing a hematologic malignancy and an even greater risk of developing cardiovascular disease.

“We knew the hematopoietic stem cells that harbor the CHIP mutations still retain the ability to differentiate into all the cells of the blood system, including immune cells, such as lymphoid cells and myeloid cells, as well as platelets and red blood cells. We hypothesized, therefore, that CHIP mutations may be associated with altered function of these innate immune cells, which lead to adverse health consequences, including increased risk of atherosclerosis, ischemic heart failure mortality, type 2 diabetes, thrombosis, and chronic obstructive lung disease,” Dr. Jaiswal said.

“In this study, we wondered if it also had an association with Alzheimer’s disease, another chronic disease of aging,” he said, explaining that the underlying mechanism tying all these conditions together appears to be inflammation: CHIP dysregulates the body’s immune response, and this results in inflammation.

Having found in the study that CHIP may actually protect against Alzheimer’s disease, the researchers now want to understand the underlying mechanism. They have several hypotheses: one is that mutations may render microglial cells better at performing one of their functions, removing the toxic amyloid and tau protein that accumulates in Alzheimer’s disease. Another pertains to replacing age-exhausted microglial cells with better-functioning versions. Animal models are being used to study these possibilities.

About the Study

Dr. Jaiswal and his colleagues analyzed data from 5,730 people (average age 60–80 years) who contributed blood samples to one of two large, ongoing precision medicine studies: Trans-Omics for Precision Medicine (TOPMed), sponsored by the National Heart, Lung, and Blood Institute; and the Alzheimer’s Disease Sequencing Project, sponsored by the National Human Genome Research Institute and the National Institute on Aging. In these samples, they looked for CHIP mutations, which are acquired after birth, and also inherited variants in the APOE gene; the APOE e4 allele significantly increases the risk of Alzheimer’s disease, whereas the e2 allele reduces risk and the e3 allele has a neutral effect.

In addition, they examined brain tissue from autopsies performed on eight donors who had CHIP, six of whom were cognitively normal when they died. These donors mostly had mutations in DNMT3A and TET2, similar to what is seen in the general population of CHIP carriers.

Key Findings

A consistent association was seen between CHIP mutations and reduced risk of Alzheimer’s disease in both the longitudinal population-based cohort and in the case-control study. A fixed-effects meta-analysis showed a 36% decreased risk for Alzheimer’s disease among CHIP carriers (odds ratio = 0.64; P = 3 × 10^-5) after adjustments for age, sex, and APOE genotype. The strongest protective effect of CHIP was seen among carriers of the APOE e3 or e4 allele, whereas none was seen for those with the e2 allele, which inherently has a protective effect on Alzheimer’s risk. “The risk reduction associated with CHIP was comparable to or greater than that of APOE e2,” Dr. Jaiswal noted.

We found the opposite of what we were expecting. CHIP surprisingly was associated with a decreased risk of Alzheimer’s disease and Alzheimer’s-related neuropathology.

— Siddhartha Jaiswal, MD

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Pathology analysis of the donated brain tissue revealed that seven of the eight CHIP carriers also had CHIP-mutated microglia. “What was even more remarkable was that in two carriers we studied in detail, 40% to 80% of the microglia had the mutations, suggesting a vast replacement of normal microglia with these mutated cells, which we hypothesize may promote protection from Alzheimer’s disease,” he said.

At the press briefing, Dr. Jaiswal was asked whether treatment of hematologic cancers in patients with CHIP abnormalities might have an adverse impact on these protective effects. “It’s certainly possible,” he said. “But overall, I’m not worried because CHIP as a whole is an adverse factor, associated with a 10- to 30-times increased risk of blood cancers and an increased risk of all-cause mortality, so as a whole I’d rather just not have CHIP.”

He was also asked whether patients with myelodysplastic syndrome and acute myeloid leukemia, who frequently harbor CHIP, might be particularly protected from Alzheimer’s disease. He said work is in progress examining the association between myelodysplastic syndrome and Alzheimer’s, which could possibly show concordant findings.² 

DISCLOSURE: Dr. Bouzid reported no conflicts of interest. Dr. Jaiswal has served as a consultant to Novartis, Foresite Labs, Genentech, and AVRO Bio; and is cofounder of and holds stock options in TenSixteen Bio. Dr. Tallman has received research funding from AbbVie, Orsenix, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen; has served on a board of directors or advisory board for AbbVie, Daiichi Sankyo, Orsenix, KAHR, Oncolyze, Jazz Pharma, Roche, Biosight, Novartis, Innate Pharma, Syros, and Kura; and has received honoraria from NYU Grand Rounds, Mayo Clinic, UC Davis, Northwell Grand Rounds, NYU Grand Rounds, Danbury Hospital Tumor Board, Acute Leukemia Forum, Miami Leukemia Symposium, New Orleans Cancer Symposium, ASH, and National Comprehensive Cancer Network.

REFERENCES

1. Bouzid H, Belk J, Jan M, et al: Clonal hematopoiesis is associated with reduced risk of Alzheimer’s disease. 2021 ASH Annual Meeting & Exposition. Abstract 5. Presented December 12, 2021.

2. Weeks LD, Marinac CR, Redd RA, et al: Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. December 7, 2021 (early release online).