Lower risk of incident dementia in males but not females with TET2 clonal hematopoiesis - a secondary analysis of the aspriin in reducing events in the elderly (ASPREE) trial Free

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for many age-related diseases, including cardiovascular disease and stroke. Dementia also increases with age, and is a major cause of disability among older adults. Surprisingly, however, some studies report that CHIP is associated with lower risk of dementia, while others have found no association. Since dementia incidence differs by sex, we assessed, separately, associations between CHIP and dementia in male and female participants of the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial.

Methods ASPREE was a large randomized controlled trial of aspirin for survival free from dementia or persistent physical disability. Participants were community-dwelling adults aged ≥70 years without underlying dementia, cardiovascular disease or known 5-year life-limiting illness. The clinical trial phase ended in mid-2017, and an observational phase continues (ASPREE-XT). Targeted CHIP sequencing was performed at baseline. CHIP was defined as one or more mutations in myeloid cancer-associated genes, at a variant allele frequency (VAF) of ≥2%. Cognitive tests were performed at baseline, years 1, 3, 5 and close-out visit for the clinical trial, and then annually through ASPREE-XT. Cognitive tests were the 3MS (for global cognition), single-letter F Controlled Oral Word Association Test (COWAT; for language and executive function), Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall task (for episodic memory) and Symbol Digit Modalities Test (SDMT; for psychomotor speed). Dementia outcomes were adjudicated (based on DSM IV criteria) by a multi-disciplinary team utilizing additional cognitive testing as well as clinical, imaging and laboratory information from medical records.

We investigated the association between CHIP and incident dementia with Cox PH regression and death as a competing risk. Exposure variables were all CHIP, gene-specific CHIP (DNMT3A, TET2) or CHIP VAF (no CHIP, CHIP VAF 2-10% or CHIP VAF ≥10%). Adjustment covariates were baseline age, obesity, hypertension, dyslipidemia, diabetes, living situation, years of formal education, family history of dementia, apoE ε4 status (0, 1 or 2 alleles), depression, smoking, alcohol, prior cancer, frailty and randomization to aspirin. Separate analyses were performed for males and females.

Additionally, we performed mixed-effects linear regression to model longitudinal change in cognitive scores in each of the four cognitive tests, as well as a global composite cognitive measure (summed z score of the four tests). The models included random (participant-specific) intercept and slope, and fixed covariates of CHIP (or subcategory), time, a CHIP-time interaction term and adjustment covariates as above.

Results Of the 9434 participants, 4367 (46%) were male and 5067 (54%) were female. CHIP was present in 2124 (22.5%), with 1150 (12.2%) DNMT3A-CHIP, 440 (4.7%) TET2-CHIP, 1592 (16.9%) VAF 2-10% and 532 (5.6%) VAF ≥10%, with no differences in prevalence between males and females.

Over a median follow up of 8.4 years, incident dementia occurred in 575 individuals. After confounder adjustment, TET2-CHIP was associated with a lower risk of dementia in males (HR 0.14 95% CI 0.03 to 0.57), but not females (HR 1.11, 95% CI 0.68 to 1.83)), heterogeneity p value = 0.007. Similar results were seen after censoring for stroke. All CHIP, DNMT3A-CHIP, and CHIP VAF were not associated with dementia risk in males or females.

Males with TET2-CHIP had significantly slower decline of global composite score (p=0.02), with non-significant trends towards slower decline in HVLT-R (p=0.07) and SDMT (p=0.05). By contrast, females with TET2-CHIP, and males or females with DNMT3A-CHIP or any CHIP, had no difference in longitudinal cognitive scores compared to those without CHIP.

ConclusionsMales, but not females, with TET2-CHIP had lower risk of incident dementia, and slower decline in composite cognitive score over time. Strengths of this study include robust adjudicated outcomes with systematic cognitive screening and comprehensive confounder adjustment. Our findings support a recent UK biobank analysis proposing TET2-CHIP is associated with lower risk of Alzheimer's dementia (PMID 40609533), but suggest an interaction between sex and TET2-CHIP that warrants further investigation to yield insights into novel sex-specific mechanisms contributing to dementia pathogenesis.