In 1,091 community-dwelling participants from the Lothian Birth Cohort 1936, tracked across three timepoints between ages 73 and 79, higher clonal haematopoiesis (CH) burden — measured via a methylation-based predictor called COMET — correlated significantly with accelerating grey matter loss over six years (standardized estimate −0.176, padj = 0.030). The atrophy pattern was left-lateralized, affecting medial temporal and parietal cortices, and spatially matched established Alzheimer's disease signatures (r = 0.357, p = 0.003). A novel companion score, CIMS, confirmed global atrophy but revealed divergent regional patterns, suggesting the two methylation tools capture distinct CH biology.
Clonal haematopoiesis — the age-related expansion of mutated blood stem cells present in roughly 10% of septuagenarians — has been associated with cardiovascular and inflammatory disease, but its role in neurodegeneration has remained genuinely contested, with prior studies producing contradictory results. This preprint, not yet peer-reviewed, is notable for its longitudinal design and relatively large imaging cohort, moving beyond the cross-sectional snapshots that plagued earlier work. The Alzheimer's-like spatial fingerprint is provocative: if CH drives neuroinflammation via dysregulated myeloid cells crossing or signaling across the blood-brain barrier, it could represent an upstream, potentially modifiable risk factor. However, important caveats apply — participants were cognitively healthy, hippocampal associations were non-significant, and causality remains unestablished. The effect size is modest, and replication in ethnically diverse cohorts is needed before CH burden can be considered a clinical biomarker for AD risk.
