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Abstract
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.
Document Type
Article
Publication Date
2025
Digital Object Identifier (DOI)
https://doi.org/10.1002/alz.70737
Funding Information
WHI; National Institutes of Health; U.S. Department of Health and Human Services, Grant/Award Numbers: 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005
Repository Citation
Jakubek, Yasminka A.; Smith, Aaron P.; Leng, Xiaoyan I.; Hall, Megan E.; Ezzat, Daniel; Pershad, Yash; Collins, Jason M.; Uddin, Md Mesbah; Fardo, David W.; Natarajan, Pradeep; Bick, Alexander G.; Kitzman, Jacob O.; Honigberg, Michael C.; Hayden, Kathleen M.; Manson, JoAnn E.; Jaiswal, Siddhartha; Whitsel, Eric A.; and Reiner, Alexander P., "Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women’s Health Initiative Memory Study" (2025). Internal Medicine Faculty Publications. 293.
https://uknowledge.uky.edu/internalmedicine_facpub/293
Notes/Citation Information
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.