Document Type

Journal Article

Publication Title

Journal of Alzheimer's Disease





First Page


Last Page


PubMed ID



IOS Press


Centre for Precision Health / School of Medical and Health Sciences

Funders / National Health and Medical Research Council

Grant Number

NHMRC Number : GNT1161706


Schäfer Hackenhaar, F., Josefsson, M., Nordin Adolfsson, A., Landfors, M., Kauppi, K., Porter, T., . . . Pudas, S. (2023). Sixteen-year longitudinal evaluation of blood-based DNA methylation biomarkers for early prediction of Alzheimer's disease. Journal of Alzheimer's Disease, 94(4), 1443-1464.


BACKGROUND: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown 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 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- (10-16 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 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- < 0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOE 4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for 4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.



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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.