Advancing Personalized Medicine in Alzheimer's Disease : Liquid Biopsy Epigenomics Unveil APOE ε4-Linked Methylation Signatures
Macías, M.
Alba-Linares, J.J. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Acha, B.
Blanco-Luquin, I.
Fernández, A.F. (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Álvarez-Jiménez, J.
Urdánoz-Casado, A.
Roldan, M.
Robles, M.
Cabezon-Arteta, E.
Alcolea, Daniel (Institut de Recerca Sant Pau)
Gordoa, J.S.R.d
Corroza, J. (Hospital Universitario de Navarra)
Cabello, C.
Erro, María Elena
Jericó, I. (Hospital Universitario de Navarra)
Fraga, M. F. (Universidad de Oviedo. Departamento de Biología de Organismos y Sistemas)
Mendioroz, Maite
Universitat Autònoma de Barcelona

Fecha:	2025
Resumen:	Recent studies show that patients with Alzheimer's disease (AD) harbor specific methylation marks in the brain that, if accessible, could be used as epigenetic biomarkers. Liquid biopsy enables the study of circulating cell-free DNA (cfDNA) fragments originated from dead cells, including neurons affected by neurodegenerative processes. Here, we isolated and epigenetically characterized plasma cfDNA from 35 patients with AD and 35 cognitively healthy controls by using the Infinium MethylationEPIC BeadChip array. Bioinformatics analysis was performed to identify differential methylation positions (DMPs) and regions (DMRs), including APOE ε4 genotype stratified analysis. Plasma pTau181 (Simoa) and cerebrospinal fluid (CSF) core biomarkers (Fujirebio) were also measured and correlated with differential methylation marks. Validation was performed with bisulfite pyrosequencing and bisulfite cloning sequencing. Epigenome-wide cfDNA analysis identified 102 DMPs associated with AD status. Most DMPs correlated with clinical cognitive and functional tests including 60% for Mini-Mental State Examination (MMSE) and 80% for Global Deterioration Scale (GDS), and with AD blood and CSF biomarkers. In silico functional analysis connected 30 DMPs to neurological processes, identifying key regulators such as SPTBN4 and APOE genes. Several DMRs were annotated to genes previously reported to harbor epigenetic brain changes in AD (HKR1, ZNF154, HOXA5, TRIM40, ATG16L2, ADAMST2) and were linked to APOE ε4 genotypes. Notably, a DMR in the HKR1 gene, previously shown to be hypermethylated in the AD hippocampus, was validated in cfDNA from an orthogonal perspective. These results support the feasibility of studying cfDNA to identify potential epigenetic biomarkers in AD. Thus, liquid biopsy could improve non-invasive AD diagnosis and aid personalized medicine by detecting epigenetic brain markers in blood.
Ayudas:	Instituto de Salud Carlos III PI20/01701
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	APOE ε4 ; Alzheimer's disease ; DNA methylation ; EPIC array ; blood ; cell-free DNA ; liquid biopsy
Publicado en:	International journal of molecular sciences, Vol. 26 Núm. 7 (april 2025) , p. 3419, ISSN 1422-0067

DOI: 10.3390/ijms26073419
PMID: 40244264

26 p, 1.9 MB

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