Clonal hematopoiesis of indeterminate potential and the risk of cognitive impairment in the Women’s Health Initiative Memory Study

Authors

• Yasminka A. Jakubek, University of KentuckyFollow
• Aaron P. Smith, University of Kentucky
• Xiaoyan I. Leng, Wake Forest School of Medicine
• Megan E. Hall, University of Kentucky
• Daniel Ezzat, Broad Institute of MIT and Harvard
• Yash Pershad, Vanderbilt University School of Medicine
• Jason M. Collins, University of North Carolina at Chapel Hill
• Md Mesbah Uddin, Broad Institute of MIT and Harvard
• David W. Fardo, University of KentuckyFollow
• Pradeep Natarajan, Broad Institute of MIT and Harvard
• Alexander G. Bick, Vanderbilt University School of Medicine
• Jacob O. Kitzman, University of Michigan - Ann Arbor
• Michael C. Honigberg, Broad Institute of MIT and Harvard
• Kathleen M. Hayden, Wake Forest University School of Medicine
• JoAnn E. Manson, Harvard Medical School
• Siddhartha Jaiswal, Stanford University School of Medicine
• Eric A. Whitsel, University of North Carolina at Chapel Hill
• Alexander P. Reiner, Fred Hutchinson Cancer Center

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

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.

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