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 ␤-amyloid 1-42 (A␤42), 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 A␤42, 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 A␤42 assay in particular had considerable intersite variability. Patients who developed AD had lower median A␤42 (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 A␤42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, PϽ.001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for A␤42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cutoffs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of A␤42/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 A␤42, 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.

Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

A tau/Aβ42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.

Objective: To determine how amyloid ␤ 42 (A␤42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. Methods:Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). A␤42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.Results: A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF A␤42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%.Conclusion: CSF A␤42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future. Neurology ® 2012;78:47-54 GLOSSARY A␤42 ϭ amyloid ␤ 42; AD ϭ Alzheimer disease; BNE ϭ BrainNet Europe; CBD ϭ corticobasal degeneration; CI ϭ confidence interval; CJD ϭ Creutzfeldt-Jakob disease; DLB ϭ dementia with Lewy bodies; FTLD ϭ frontotemporal lobar degeneration; IQR ϭ interquartile range; MMSE ϭ Mini-Mental State Examination; NINDS ϭ National Institute of Neurological Disorders and Stroke; OD ϭ other types of dementia; OR ϭ odds ratio; p-tau ϭ phosphorylated tau; PSP ϭ progressive supranuclear palsy; PSY ϭ psychiatric disorder; SMC ϭ subjective memory complaints; t-tau ϭ total tau; VaD ϭ vascular dementia.

BACKGROUND:To improve ante mortem diagnostic accuracy of Alzheimer disease (AD), measurement of the biomarkers amyloid-␤(1-42) (A␤42), total tau (Tau), and tau phosphorylated at threonine 181 (pTau) in cerebrospinal fluid (CSF) has been proposed. We have used these markers and evaluated their performance.