Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease

Background: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-beta-amyloid (A beta) drug candidate affects both A beta metabolism and plaque load as well as downstream pathogenic mechanisms. Objective: To evaluate the effect of the anti-A beta mono-clonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting A beta homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. Design: Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration. Setting: Academic centers in the United States (Study 201) and England and Finland (Study 202). Patients: Forty-six patients with mild to moderate Alzheimer disease. Interventions: Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups. Main Outcome Measures: Changes between end of study and baseline in the exploratory CSF biomarkers A beta 1-42, A beta X-42, A beta X-40; total tau (T-tau); and phosphorylated tau (P-tau). Results: Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF A beta. Conclusions: To our knowledge, this study is the first to show that passive A beta immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-A beta drugs in clinical trials.