title: Plasma miR-34a-5p and miR-545-3p as Early Biomarkers of Alzheimer's Disease: Potential and Limitations.
abstract: Plasma microRNAs (miRNAs) have been proposed as potential biomarkers in Alzheimer's disease (AD). Here, we explored their use as early sensors of the preclinical phase of the disease, when brain pathology is being developed and no cognitive loss is detected. For this purpose, we analyzed a set of ten mature plasma miRNAs in symptomatic patients with AD from a cohort that also included healthy controls (HC) and patients with preclinical Alzheimer's disease (PAD) (cohort 1). Plasmas from subjects with Parkinson's disease (PD) were used to control for disease specificity. We found that miR-15b-5p, miR-34a-5p, miR-142-3p, and miR-545-3p levels significantly distinguished AD from PD and HC subjects. We next examined the expression of these four miRNAs in plasma from subjects with PAD. Among these, miR-34a-5p and miR-545-3p presented good diagnostic accuracy to distinguish both AD and PAD from HC subjects, according to the receiver operating characteristic (ROC) curve analysis. Both miRNAs also demonstrated a significant positive correlation with Aβ1-42 levels in cerebrospinal fluid (CSF). Taking into account the clinical potential of these findings, we decided to validate the diagnostic accuracy of miR-34a-5p and miR-545-3p in plasma samples from an independent cohort (cohort 2), in which we did not observe the alterations described by us and others in AD and PAD samples. Although miR-34a-5p and miR-545-3p might be promising early biomarker candidates for AD, our study highlights possible sources of variability in miRNA analysis across hospitals, which currently prevents their use as reliable clinical tools.
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.|Unitat de Farmacologia, Facultat de Farmàcia, Institut de Neurociències, Universitat de Barcelona and CIBERNED, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cosín-Tomás
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Antonell
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.affiliation: Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau de Barcelona, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcolea
authors.affiliation: Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau de Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Parkinson's Disease and Movement Disorders Unit, Institut de Neurociències Hospital Clínic, CIBERNED, Barcelona, Catalonia, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Ezquerra
authors.affiliation: Memory Unit, Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau de Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Parkinson's Disease and Movement Disorders Unit, Institut de Neurociències Hospital Clínic, CIBERNED, Barcelona, Catalonia, Spain.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Martí
authors.affiliation: Unitat de Farmacologia, Facultat de Farmàcia, Institut de Neurociències, Universitat de Barcelona and CIBERNED, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Valle
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: José Luís
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain. coral.sanfeliu@iibb.csic.es.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. coral.sanfeliu@iibb.csic.es.
authors.forename: Coral
authors.identifier: http://orcid.org/0000-0002-9004-1206
authors.initials: C
authors.lastname: Sanfeliu
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain. perlakaliman@gmail.com.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. perlakaliman@gmail.com.|Center for Mind and Brain, University of California Davis, Davis, CA, USA. perlakaliman@gmail.com.
authors.forename: Perla
authors.initials: P
authors.lastname: Kaliman
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D015415:Biomarkers / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D012372:ROC Curve
chemical_list: D015415:Biomarkers; C000594767:MIR545 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs
keywords: Alzheimer’s disease; Plasma biomarker; Preclinical; miR-34a-5p; miR-545-3p; miRNA