Clinical validity of cerebrospinal fluid Aβ42, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.
Novel diagnostic criteria for Alzheimer's disease (AD) incorporate biomarkers, but their maturity for implementation in clinical practice at the prodromal stage (mild cognitive impairment [MCI]) is unclear. Here, we evaluate cerebrospinal fluid (CSF) β-amyloid42(Aβ42), total tau, and phosphorylated tau in the light of a 5-phase framework for biomarker development. Ample evidence is available for phase 1 (identifying useful leads) and phase 2 (assessing the accuracy for AD dementia versus controls) for CSF biomarkers. Phase 3 (utility in MCI) is partially achieved. In cohorts with long follow-up time, CSF Aβ42, total tau, and phosphorylated tau have high diagnostic accuracy for MCI due to AD. Phase 4 (performance in real world) is ongoing, and phase 5 studies (quantify impact and costs) are to come. Our results highlight priorities to pursue and to enable the proper use of CSF biomarkers in the clinic. Priorities are to reduce measurement variability by introduction of fully automated assay systems; to increase diagnostic specificity toward non-AD neurocognitive diseases at the MCI stage; and to clarify the role of CSF biomarkers versus other biomarker modalities in clinical practice and in design of clinical trials. These efforts are currently ongoing.
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden; Department of Neurology, Skåne University Hospital, Lund, Sweden. Electronic address: niklas.mattsson@med.lu.se.
Niklas
N
Mattsson
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Anders
A
Lönneborg
Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Fatebenefratelli, Brescia, Italy; LANVIE, Laboratory of Neuroimaging of Aging, University of Geneva, Geneva, Switzerland.
Marina
M
Boccardi
Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden.
Kaj
K
Blennow
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden. Electronic address: oskar.hansson@med.lu.se.
Oskar
O
Hansson
D000544:Alzheimer Disease / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000175:diagnosis; D003704:Dementia / Q000175:diagnosis; D042241:Early Diagnosis; D006801:Humans; D019965:Neurocognitive Disorders / Q000175:diagnosis; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D015203:Reproducibility of Results; D016875:tau Proteins / Q000134:cerebrospinal fluid*
D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
5-Phases; Alzheimer's disease; Beta-amyloid; Biomarker development; Biomarker-based diagnosis; Cerebrospinal fluid; Early diagnosis; Phosphorylated tau; Tau