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.