CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment

Abstract

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-amyloid1-42 (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