{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:27:42Z","timestamp":1791239262777,"version":"4.1.0"},"reference-count":107,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T00:00:00Z","timestamp":1692057600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:p>Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer\u2019s disease (AD) prediction. Objective: Testing long-term predictive ability (&gt;15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers. Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10\u201316 years), and post-AD-onset time-points. Results: EAA did not differentiate cases from controls during the follow-up time (p\u200a&gt;\u200a0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-&lt;0.00001). Our longitudinally-derived panel replicated nominally (p\u200a=\u200a0.012) in an external cohort (n\u200a=\u200a146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE \u025b4-carriership (OR\u200a=\u200a1.38 per 1 SD DNAm score increase versus OR\u200a=\u200a13.58 for \u025b4-allele carriage; AUCs\u200a=\u200a77.2% versus 87.0%). Literature review showed low overlap (n\u200a=\u200a4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.<\/jats:p>","DOI":"10.3233\/jad-230039","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T11:20:34Z","timestamp":1688124034000},"page":"1443-1464","source":"Crossref","is-referenced-by-count":11,"title":["Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"94","author":[{"given":"Fernanda","family":"Sch\u00e4fer Hackenhaar","sequence":"first","affiliation":[{"name":"Department of Integrative Medical Biology, Ume\u00e5 University, Ume\u00e5, Sweden"},{"name":"Ume\u00e5 Center for Functional Brain Imaging, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Australian Imaging Biomarkers and Lifestyle Study","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Josefsson","sequence":"additional","affiliation":[{"name":"Ume\u00e5 Center for Functional Brain Imaging, Ume\u00e5 University, Ume\u00e5, Sweden"},{"name":"Department of Statistics, USBE, Ume\u00e5 University, Ume\u00e5, Sweden"},{"name":"Center for Ageing and Demographic Research, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelie","family":"Nordin Adolfsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias","family":"Landfors","sequence":"additional","affiliation":[{"name":"Department of Medical Biosciences, Pathology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Kauppi","sequence":"additional","affiliation":[{"name":"Department of Integrative Medical Biology, Ume\u00e5 University, Ume\u00e5, Sweden"},{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenielle","family":"Porter","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia"},{"name":"Curtin Medical School, Curtin University, Bentley, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidija","family":"Milicic","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon M.","family":"Laws","sequence":"additional","affiliation":[{"name":"Centre for Precision Health, Edith Cowan University, Joondalup, WA, Australia"},{"name":"Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia"},{"name":"Curtin Medical School, Curtin University, Bentley, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Hultdin","sequence":"additional","affiliation":[{"name":"Department of Medical Biosciences, Pathology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Adolfsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, 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