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–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.