Clonal hematopoiesis of indeterminate potential and risk of neurodegenerative diseases
Abstract
Background Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases. Objective To estimate the risk of neurodegenerative diseases among individuals with CHIP. Methods We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP. Results We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01-1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05-1.63) and ALS (HR 1.50, 95% CI 1.05-2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97-1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96-1.17), AD (HR 1.04, 95% CI 0.88-1.23), and PD (HR 1.02, 95% CI 0.86-1.21). The risk increase in any neurodegenerative…
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Large-scale population-based analyses suggest that CHIP carriers may exhibit a significantly reduced incidence of clinically diagnosed AD.
“evidence for protective effects stems from large-scale population-based analyses, encompassing cohorts ranging from approximately 5000 to over 500,000 individuals, suggest that CHIP carriers may exhibit a significantly reduced incidence of clinically diagnosed AD [10,11].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [11]
Gene-specific effects, clonal burden, host genetic background, and neurovascular integrity all shape whether CHIP-derived immune cells exert protective or pathogenic influences in the aging brain.
“Gene-specific effects, clonal burden, host genetic background, and neurovascular integrity all shape whether CHIP-derived immune cells exert protective or pathogenic influences in the aging brain [10,11,13,19,33,34].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [11]
The lack of AD association in Liu et al. is likely constrained by the cohort's younger demographic and the use of ICD-based diagnostic adjudication, leading to underestimation of AD incidence and biomarker-confirmed cases.
“a finding likely constrained by the cohort’s younger demographic and the use of ICD-based diagnostic adjudication, which together lead to a significant underestimation of AD incidence and biomarker-confirmed cases.”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [11]
DNMT3A-mutant CHIP has shown protective associations with cognitive outcomes in some population-based and clinical cohorts as well as specific subgroups, particularly for larger clones and in select disease contexts.
“DNMT3A-mutant CHIP has shown protective associations with cognitive outcomes in some population-based and clinical cohorts as well as specific subgroups in these studies, particularly for larger clones and in select disease contexts [10,11,19,33].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [11]
Liu et al. observed a modest increase in the risk of any neurodegenerative disease among CHIP carriers, with stronger associations for vascular neurodegenerative diseases and ALS, but no significant association for Alzheimer's disease specifically.
“Liu et al. observed a modest increase in the risk of any neurodegenerative disease among CHIP carriers, with stronger associations for vascular neurodegenerative diseases and ALS; however, no significant association was detected for Alzheimer’s disease specifically [11]”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [11]
Cites
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310 · see citing works
Clonal hematopoiesis in human aging and disease
Jaiswal, S., & Ebert, B. L. (2019) · Science · doi:10.1126/science.aan4673 · Cited by 1,156 · see citing works
Clonal hematopoiesis is associated with protection from Alzheimer’s disease
Bouzid, H., Belk, J. A., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M. R., Ahmad, H., Nachun, D., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02397-2 · Cited by 169 · see citing works
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Matatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., et al. (2025) · Cell Stem Cell · doi:10.1016/j.stem.2025.06.006 · Cited by 23 · see citing works
<i>Tet2</i> and <i>Jak2</i> clonal hematopoiesis do not modify murine tauopathy
Gaebel, L., Gerhardt, T., Khamhoung, A., Huynh, P., Heiser, M., Brisnovali, N. F., Jacob, W., Yates, A. G., Douglas, A., Fidler, T., et al. (2026) · Journal of Alzheimer’s Disease · doi:10.1177/13872877261458734 · Cited by 1 · see citing works
Kopp, K., Silva, P., Damm, F., & Cosma, N. C. (2026) · Biomedicines · doi:10.3390/biomedicines14051012
- Authors
- Liu, X., Xue, H., Wirdefeldt, K., Song, H., Smedby, K., Fang, F., & Liu, Q.
- Affiliations
- Fudan University (CN)
- Nanfang Hospital (CN)
- Karolinska Institutet (SE)
- Sichuan University (CN)
- Karolinska University Hospital (SE)
- Corresponding author
- Liu, Qianwei
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2024-07-29
- Volume
- 296
- Issue
- 4
- Pages
- 327-335
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- OpenAlex
- W4401094928
- Cited by
- 29
- References
- 3
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 1
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Southern Medical University (2023G001)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- clonal hematopoiesis of indeterminate potential, neurodegenerative diseases, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, DNMT3A mutation, ASXL1 mutation, SRSF2 mutation, disease risk
- MeSH terms
- Clonal Hematopoiesis, DNA Methyltransferase 3A, Aged, Amyotrophic Lateral Sclerosis, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Female, United Kingdom, Humans, Male, Middle Aged, Parkinson Disease, Repressor Proteins, Risk Factors, Cohort Studies, Neurodegenerative Diseases, Dioxygenases
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