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A Non-invasive Epigenetic Strategy Improves Alzheimer's Disease Diagnosis

January 29, 2025
Table of Contents:
Introduction: The Pressing Need for Non-invasive Alzheimer's Disease Biomarkers
Alzheimer's disease – a progressive neurodegenerative condition – represents an ever-increasing problem as a more significant proportion of people across the world live till old age. Currently understood diagnostic biomarkers, such as extracellular β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau protein (pTau) (McKhann et al.), remain difficult to access, which makes the accurate diagnosis of patients using non-invasive means extremely challenging.
Blood-based biomarkers represent a potentially exciting and non-invasive solution to diagnostic problems in a range of diseases, including Alzheimer's disease. Previous studies have revealed that the measurement of phosphoforms of Tau in blood plasma can predict the progression of Alzheimer's disease to dementia (e.g., plasma pTau181; Thijssen et al. and Karikari et al.); however, this approach remains far from routine application in clinical practice.
Researchers headed by Maite Mendioroz (Navarrabiomed, as part of the iBEAS Study Group) knew that epigenetics likely played a critical role in Alzheimer's disease development and could provide a wealth of non-invasive blood-borne biomarkers. Indeed, a range of previous studies that explored blood-based DNA methylation markers in Alzheimer's disease patients suggested the huge potential of this approach; now, researchers from the Mendioroz laboratory sought to explore the diagnostic potential of a blood-based DNA methylation marker panel composed of multiple CpG sites linked to multiple genes and whether this panel could improve the diagnostic value of a Tau phosphoform detected in blood plasma (Acha et al.).
Blood-based Epigenetic Analysis Provides a Significantly Improved Diagnostic Model
Acha et al. carried out a case-control study by measuring DNA methylation levels at 44 CpG sites associated with 19 differentially-methylated Alzheimer's disease-associated genes via bisulfite pyrosequencing in peripheral blood leukocytes of 80 probable Alzheimer's disease dementia patients and 100 age-matched and sex-matched cognitively healthy controls. Bivariate analysis revealed statistically significant differences between Alzheimer's disease patients and healthy controls at 11 of the 44 CpGs, corresponding to 9 genes.
The subsequent development of variable logistic regression models revealed that a panel that integrated DNA methylation levels at the nucleoredoxin (NXN), triggering receptor expressed on myeloid cells like 2 (TREML2), ATP-binding cassette subfamily A member 7 (ABCA7), and homeobox A3 (HOXA3) genes combined with plasma pTau181 levels provided a significantly improved diagnostic performance (83.30% sensitivity and 90.00% specificity) when compared to an adjusted pTau181-only-based model. Overall, these hugely encouraging findings suggested the considerable potential of non-invasive epigenetic biomarkers in Alzheimer's disease diagnosis.
The authors also undertook a sex-stratified analysis, which demonstrated that only HOXA3 DNA methylation levels (and plasma pTau181 levels) were consistently associated with Alzheimer's disease, suggesting that HOXA3 methylation levels displayed the most substantial effect of all variables and, additionally, the existence of sex-specific differences in DNA methylation in affected patients.
A Non-invasive Epigenetic Strategy Towards Improved Alzheimer's Disease Diagnosis
Overall, this exciting study reveals that a panel of non-invasively detected epigenetic biomarkers can differentiate Alzheimer's disease patients from healthy controls, suggesting the power of blood-based DNA methylation in disease diagnosis. The authors hope these positive results will soon be evaluated/externally validated in larger multicentric cohorts and will prompt the development of a diagnostic tool to aid disease management.
For more on how the non-invasive analysis of DNA methylation biomarkers could prompt significant improvements in Alzheimer's diagnosis, see Neurology, December 2023.
About the author

Stuart P. Atkinson, Ph.D.
Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!
Contact Stuart on X with any questions
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