title: Cerebrospinal fluid biomarkers for Alzheimer's disease: current limitations and recent developments.
abstract: OBJECTIVE
  To give perspectives on current limitations and recent developments in the field of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD).
  
  
  RESULTS
  Three CSF biomarkers for the neuropathological hallmarks of Alzheimer's disease, namely total tau (T-tau), phospho-tau (P-tau) and the 42 amino acid form of amyloid β (Aβ42), reflecting neurodegeneration, neurofibrillary tangles and amyloid/senile plaques, respectively, have been developed, validated and incorporated into new diagnostic criteria for the disease. Thanks to global collaborative research efforts, these have been to a large extent a success story but there are a number of limitations that warrant further research and discussion. First, bias and random variation in biomarker measurements both within and between laboratories remain an issue. Second, current markers only reflect part of the pathology underlying Alzheimer's disease; new markers of synaptic dysfunction, microglial activation and protein aggregates that are frequently seen alongside plaque and tangle pathology are needed. Third, fluid markers do not represent the anatomic location of any pathological change; CSF markers may be complemented with high resolution molecular imaging techniques.
  
  
  CONCLUSIONS
  There has been considerable progress in the validation and standardization of assays for CSF T-tau, P-tau and Aβ42. Novel biomarkers for synaptic function, microglial activation and protein accumulations other than tau and Aβ are in development. Future fluid biomarker research should be conducted in close collaboration with molecular imaging specialists.
authors.affiliation: aClinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden bDepartment of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D006801:Humans; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins