Context  Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted.

Objective  To determine the diagnostic accuracy of CSF β-amyloid_1-42 (Aβ42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI.

Design, Setting, and Participants  The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia.

Main Outcome Measures  Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Aβ42, T-tau, and P-tau for identifying incipient AD.

Results  During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Aβ42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Aβ42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Aβ42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Aβ42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Aβ42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%.

Conclusions  This multicenter study found that CSF Aβ42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

Author Affiliations: Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden (Drs Mattsson, Zetterberg, Jonsson, Rosén, Wallin, and Blennow); Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden (Drs Hansson and Minthon); Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden (Drs Andreasen, Eriksdotter Jönhagen, and Winblad); Clinica Neurologica, University of Perugia, Perugia, Italy (Dr Parnetti); Department of Neurology and Brain Research Unit, Clinical Research Centre/Mediteknia, University of Kuopio and Kuopio University Hospital, Kuopio, Finland (Drs Herukka and Pirttilä); Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, the Netherlands (Drs van der Flier, Blankenstein, and Scheltens); Department of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin, Ireland (Drs Ewers and Hampel); Department of Psychiatry, Alzheimer Memorial Center, Ludwig-Maximilian University, Munich, Germany (Drs Ewers and Hampel); New York University, School of Medicine, Center for Brain Health, New York, New York (Drs Rich and de Leon); Sektion Gerontopsychiatrie Universität Heidelberg, Germany (Drs Kaiser and Schröder); Laboratory of Pediatrics and Neurology, Radboud University Medical Centre, Nijmegen, the Netherlands (Dr Verbeek); Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Papanicolaore General Hospital, Thessaloniki, Greece (Dr Tsolaki); Centre for Clinical Neuroscience Research, Stavanger University Hospital, Stavanger, Norway (Drs Mulugeta and Aarsland); Department of Psychiatry and Neuropsychology, Institute of Brain and Behavior, University of Maastricht, Maastricht, the Netherlands (Dr Jelle-Visser); and Department of Neuroscience and Locomotion, Division of Geriatric Medicine, Linköpings Universitet, Linköping, Sweden (Dr Marcusson).