{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:47:11Z","timestamp":1792583231920,"version":"4.5.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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\u2010based predictor of mortality, and examined the contribution of smoking\u2010related DNA methylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010reported and DNA methylation\u2010derived), followed by random\u2010effects meta\u2010analysis. Component\u2010level analyses examined smoking\u2010related DNA methylation, inflammatory markers, and glucose metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients with frontotemporal dementia showed increased GrimAge2\u2010derived epigenetic age acceleration (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20091.17\u2009\u00b1\u20090.36, 95% CI 0.46\u20131.88,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001) compared with controls. Component\u2010level analyses showed increased smoking\u2010related DNA methylation, systemic inflammation (tissue inhibitor of metalloproteinases 1, C\u2010reactive protein), and glucose metabolism (glycated hemoglobin; all\n                      <jats:italic>p\u2009&lt;<\/jats:italic>\n                      \u20090.05). Adjustment for smoking\u2010related DNA methylation was associated with attenuation of the effect estimate by approximately 48% (epigenetic age acceleration:\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.62\u2009\u00b1\u20090.32, 95% CI \u22120.01\u20131.24,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.053).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Accelerated epigenetic aging in frontotemporal dementia is associated with GrimAge2\u2010derived DNA methylation patterns linked to smoking, inflammation, and metabolic pathways. These findings raise the possibility that smoking\u2010related DNA methylation reflects differences in smoking exposure or disease\u2010related behavioral changes captured by GrimAge2. ANN NEUROL 2026<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78395","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:33:48Z","timestamp":1792582428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Accelerated Epigenetic Aging in Frontotemporal Dementia Highlights Smoking, Inflammation, and Metabolic Signals"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5652-4897","authenticated-orcid":false,"given":"Daphne","family":"Nijland","sequence":"first","affiliation":[{"name":"Genomics of Neurodegenerative Diseases and Aging Department of Human Genetics Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven J.","family":"van der Lee","sequence":"additional","affiliation":[{"name":"Genomics of Neurodegenerative Diseases and Aging Department of Human Genetics Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eska Marye","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naren","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles  Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9595-7221","authenticated-orcid":false,"given":"Sterre C.M.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Everard G.B.","family":"Vijverberg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henne","family":"Holstege","sequence":"additional","affiliation":[{"name":"Genomics of Neurodegenerative Diseases and Aging Department of Human Genetics Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande A.L.","family":"Pijnenburg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Alzheimer Center Amsterdam Amsterdam UMC Location VUmc  Amsterdam the Netherlands"},{"name":"Amsterdam Neuroscience  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel A.","family":"Ophoff","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior University of California, Los Angeles  Los Angeles CA USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles  Los Angeles CA 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