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

Nijland D, van der Lee SJ, de Haan EM, +6 more, Reus LM.

Journal ArticleAbstract only — full text under license

AI summary — for doctors, generated from the abstract only

People with frontotemporal dementia show accelerated epigenetic aging by GrimAge2, linked to smoking-related methylation, inflammation and glucose metabolism.

What was studied

Blood DNA methylation analysis in two cohorts (313 patients and 121 controls; 102 patients and 102 controls) with meta-analysis, adjusted for sex, cell proportions and smoking.

Key findings

FTD patients had greater GrimAge2 age acceleration than controls (β 1.17, 95% CI 0.46-1.88, p=0.001).
Components showed more smoking-related methylation, inflammation (TIMP1, CRP) and glucose metabolism (HbA1c).

Clinical relevance

Suggests systemic and modifiable factors may be associated with FTD biology.

Who should care

Neurology

Limitations

Cross-sectional associations with no causal direction, and the abstract is truncated.

No practice change; reinforces attention to smoking and metabolic health.

This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.

Abstract

Objective

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, a DNA methylation-based predictor of mortality, and examined the contribution of smoking-related DNA methylation.

Methods

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.

Results

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).

Interpretation

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.

DOI

10.1002/ana.78395

PMID

42904574

Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.

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