Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women’s Health Initiative Memory Study
Open accessAbstract
INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) confers an increased risk of several chronic aging‐related diseases. Paradoxically, CHIP was associated with lower risk of dementia in recent studies. METHODS: We examined associations between baseline CHIP and incident mild cognitive impairment (MCI) and/or probable dementia in the Women's Health Initiative Memory Study. CHIP was detected using blood‐based targeted sequencing. Cox proportional hazards models examined time to onset of cognitive impairment, adjusting for traditional risk factors. RESULTS: Using a conventional variant allele fraction (VAF) threshold of 2%, CHIP was not associated with incident cognitive impairment. The presence of larger CHIP clone (VAF ≥ 8%) was associated with a lower incidence of adjudicated probable dementia (hazard ratio = 0.62 [95% confidence interval = 0.41 to 0.94], p = 0.025), while the association with the composite outcome MCI/probable dementia was weaker and overlapped 1.0. DISCUSSION: The association of CHIP with lower risk of cognitive impairment in postmenopausal women may be dependent on VAF and impairment severity. Highlights: The WHIMS comprises ∼5000 postmenopausal women, followed for up to 25 years. CHIP was associated with reduced risk of adjudicated probable dementia in WHIMS. Large CHIP clones (> 8% VAF), but not small clones (<8% VAF), showed an association. CHIP was not associated with MCI in the WHIMS cohort.
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In the Women's Health Initiative Memory Study, larger CHIP clones (≥8% VAF) were associated with a significantly reduced risk of clinically diagnosed probable dementia over up to 25 years, but no association was observed for mild cognitive impairment.
“In the Women’s Health Initiative Memory Study, larger CHIP clones (≥8% VAF) were associated with a significantly reduced risk of clinically diagnosed probable dementia over a long-term follow-up of up to 25 years. By contrast, no association was observed for mild cognitive impairment [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 [33]
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Experimental — accuracy not yet measuredGene-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 [33]
The Discussion (page not provided) reports that associations with cognitive impairment varied by CHIP driver gene, clone size, and APOE genotype. It does not establish that neurovascular integrity determines whether CHIP-derived immune cells are protective or pathogenic, or demonstrate that these factors causally shape the cells’ effects in the brain. (LLM, conf=0.84)
Experimental — accuracy not yet measuredProtective associations with AD and attenuated neuropathology were observed predominantly in individuals carrying large CHIP clones, typically defined by VAF thresholds of ≥8%, whereas smaller clones showed weaker, null, or inconsistent associations.
“In particular, protective associations with AD and attenuated neuropathology were observed predominantly in individuals carrying large CHIP clones, typically defined by VAF thresholds of ≥8%; however, smaller clones showed weaker, null, or inconsistent associations [10,33].”
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 [33]
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Experimental — accuracy not yet measuredDNMT3A-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 [33]
Clonal burden is a critical determinant of phenotypic effect.
“However, several studies have demonstrated that clonal burden is a critical determinant of phenotypic effect.”
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 [33]
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Cites
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Cited by
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<i>Tet2</i> and <i>Jak2</i> clonal hematopoiesis do not modify murine tauopathy
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- Authors
- Jakubek, Y. A., Smith, A. P., Leng, X. I., Hall, M. E., Ezzat, D., Pershad, Y., Collins, J. M., Uddin, M. M., Fardo, D. W., Natarajan, P., Bick, A. G., Kitzman, J. O., Honigberg, M. C., Hayden, K. M., Manson, J. E., Jaiswal, S., Whitsel, E. A., & Reiner, A. P.
- Affiliations
- University of Kentucky (US)
- Wake Forest University Health Sciences (US)
- Broad Institute (US)
- Vanderbilt University (US)
- University of North Carolina at Chapel Hill (US)
- University of Michigan (US)
- Brigham and Women's Hospital (US)
- Stanford Medicine (US)
- Division of Public Health Sciences Fred Hutchinson Cancer Center Seattle Washington USA
- Corresponding author
- Jakubek, Yasminka A.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2025-09-30
- Volume
- 21
- Issue
- 10
- Pages
- e70737-e70737
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC12481165
- OpenAlex
- W4414669381
- Cited by
- 9
- References
- 3
- Citations by year
- 2026: 9
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc)
- Funders
- Women's Health Initiative
- National Institutes of Health
- U.S. Department of Health and Human Services (75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- clonal hematopoiesis of indeterminate potential, cognitive impairment
- MeSH terms
- Clonal Hematopoiesis, Aged, Aged, 80 and over, Dementia, Female, Humans, Middle Aged, Risk Factors, Incidence, Proportional Hazards Models, Women's Health, Cognitive Dysfunction
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