Accelerated Epigenetic Aging in Frontotemporal Dementia Highlights Smoking, Inflammation, and Metabolic Signals.

<h4>Objective</h4>Epigenetic clocks are biomarkers of biological aging influenced by lifestyle and systemic factors. Accelerated epigenetic aging has been associated with neurodegeneration, but its relevance in frontotemporal dementia is unclear. We investigated biological aging in frontotemporal dementia using the GrimAge2 epigenetic clock(definition), a DNA methylation-based predictor of mortality, and examined the contribution of smoking-related DNA methylation.<h4>Methods</h4>Peripheral blood DNA methylation data from frontotemporal dementia patients and controls from 2 independent cohorts were analyzed (Amsterdam Dementia Cohort: 313 patients, 121 controls; Genetic Investigation in Frontotemporal Dementia study: 102 patients, 102 controls). GrimAge2 was used to estimate epigenetic age acceleration. Associations with diagnosis were assessed using linear regression models adjusted for sex, estimated cell type proportions, and smoking (self-reported and DNA methylation-derived), followed by random-effects meta-analysis. Component-level analyses examined smoking-related DNA methylation, inflammatory markers, and glucose metabolism.<h4>Results</h4>Patients with frontotemporal dementia showed increased GrimAge2-derived epigenetic age acceleration (β = 1.17 ± 0.36, 95% CI 0.46-1.88, p = 0.001) compared with controls. Component-level analyses showed increased smoking-related DNA methylation, systemic inflammation (tissue inhibitor of metalloproteinases 1, C-reactive protein), and glucose metabolism (glycated hemoglobin; all p < 0.05). Adjustment for smoking-related DNA methylation was associated with attenuation of the effect estimate by approximately 48% (epigenetic age acceleration: β = 0.62 ± 0.32, 95% CI -0.01-1.24, p = 0.053).<h4>Interpretation</h4>Accelerated epigenetic aging in frontotemporal dementia is associated with GrimAge2-derived DNA methylation patterns linked to smoking, inflammation, and metabolic pathways. These findings raise the possibility that smoking-related DNA methylation reflects differences in smoking exposure or disease-related behavioral changes captured by GrimAge2. ANN NEUROL 2026.