Clonal Hematopoiesis and the Risk of Dementia: The Monzino 80-Plus Population-Based Study

Clonal hematopoiesis of indeterminate potential (CHIP) describes individuals with hematologic malignancy-associated mutations in blood or marrow (with variance allele frequency (VAF) ≥2%) but without other diagnostic criteria for a hematologic malignancy. CHIP is associated with an increased risk of cancers, particularly myeloid neoplasms, and chronic inflammatory diseases such as coronary heart disease. A recent study (PMID: 37322115) has suggested that CHIP may have a potential protective role against Alzheimer's disease, a condition where brain-resident myeloid cells are believed to play a significant role. This finding has prompted further investigation into the association between CHIP and dementia. In this study, we aimed to explore the relationship between CHIP and both dementia and Alzheimer's disease within a cohort of 735 oldest-old individuals from the Monzino 80-plus population-based study (PMID: 31786127). The study population had a median age of 90 years and was enrolled through a door-to-door survey conducted in the province of Varese, Italy, from 2002 to 2017 (15-year follow-up). Participants underwent an extensive neuropsychological assessment to evaluate cognitive status and diagnose dementia, according to DMS-IV criteria at study entry and during follow-up visits. Targeted next-generation sequencing (NGS) was performed to identify CHIP-related mutations in peripheral blood. Variant calling was performed using Shearwater algorithm (PMID:24443148). The prevalence of CHIP in the cohort (defined according a VAF threshold ≥2%) was 17.4%, and increased significantly with age, particularly among individuals over 100 years old (P<0.001). The most frequently mutated genes were TET2, DNMT3A, and ASXL1. Dementia prevalence in the study population was 37.9%. There was no significant association observed between CHIP and the prevalence of dementia at baseline (OR: 1.22, 95% CI: 0.82-1.79, P=0.327), even after adjusting for potential confounders such as age, sex, education, and ApoE genotype (OR: 1.06, 95% CI: 0.67-1.66, P=0.814). Over a median follow-up period of 36 months, dementia incidence was assessed among 435 subjects for whom follow-up data were available, with 218 subjects developing dementia during this time, resulting in an overall incidence rate of 12.8%. Statistical analyses showed no significant correlation between CHIP and incident dementia, even after accounting for potential confounders (HR: 1.11, 95% CI: 0.75-1.64, P=0.616). These results remained consistent even when considering the number of mutations, VAF, or specific mutated genes as DNMT3A and TET2. We then specifically examined the relationship between CHIP and Alzheimer's disease. In preliminary analysis, among incident dementia cases 86 matched a diagnosis of Alzheimer's disease. No significant association was found between CHIP and the incidence of Alzheimer's disease, even after adjusting for age, sex, and education (HR: 0.79, 95% CI: 0.42-1.50 P = 0.474). In conclusion, our study suggests that CHIP is not significantly associated with either prevalent or incident dementia, nor Alzheimer's disease in the oldest-old population. Additional studies are needed to fully understand the implications of CHIP in aging and its potential impact on neurodegenerative diseases. The interplay between CHIP, inflammation, and neurodegeneration warrants further investigation to provide valuable insights into the pathophysiological processes involved.