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Sixteen-year longitudinal evaluation of blood-based DNA methylation biomarkers for early prediction of Alzheimer’s disease
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).ORCID iD: 0000-0002-9395-2216
Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.ORCID iD: 0000-0002-1812-3581
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.ORCID iD: 0000-0002-8114-7615
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2023 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 94, no 4, p. 1443-1464Article in journal (Refereed) Published
Abstract [en]

Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, hasshown promise for Alzheimer’s disease (AD) prediction.Objective: Testing long-term predictive ability (>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 16years before clinical onset, and post-onset follow-up. NovelDNAmbiomarkers were generated with epigenome-wide LMMs,and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10–16 years), and post-AD-onset time-points.

Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkersshowed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions(p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE 4-carriership(OR = 1.38 per 1 SD DNAmscore increase versus OR= 13.58 for 4-allele carriage; AUCs = 77.2% versus 87.0%). Literaturereview showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with ouridentified CpGs.

Conclusion: The limited predictive value of EAA for AD extends prior findings by considering a longer follow-up time, andwith appropriate control for age, sex, APOE, and blood-cell proportions. Results also highlight challenges with replicatingdiscriminatory or predictive CpGs across studies.

Place, publisher, year, edition, pages
IOS Press , 2023. Vol. 94, no 4, p. 1443-1464
Keywords [en]
Alzheimer’s disease, biomarkers, DNA methylation, epigenomics, longitudinal studies
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:umu:diva-214007DOI: 10.3233/jad-230039PubMedID: 37393498Scopus ID: 2-s2.0-85168428453OAI: oai:DiVA.org:umu-214007DiVA, id: diva2:1793748
Funder
Swedish Research Council, 2018-01729The Kempe Foundations, JCK-1922.1Available from: 2023-09-02 Created: 2023-09-02 Last updated: 2024-04-08Bibliographically approved

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Schäfer Hackenhaar, FernandaJosefsson, MariaNordin Adolfsson, AnnelieLandfors, MattiasKauppi, KarolinaHultdin, MagnusAdolfsson, RolfDegerman, SofiePudas, Sara

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Schäfer Hackenhaar, FernandaJosefsson, MariaNordin Adolfsson, AnnelieLandfors, MattiasKauppi, KarolinaHultdin, MagnusAdolfsson, RolfDegerman, SofiePudas, Sara
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Department of Integrative Medical Biology (IMB)Umeå Centre for Functional Brain Imaging (UFBI)Centre for Demographic and Ageing Research (CEDAR)StatisticsPsychiatryPathologyDepartment of Clinical Microbiology
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