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–β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.
Objective
To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ 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 Aβ1-42, AβX-42, AβX-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 Aβ.
Conclusions
To our knowledge, this study is the first to show that passive Aβ 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-Aβ drugs in clinical trials.
Trial Registrations
clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.