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

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.