Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab

Neurology. 2018 Mar 6;90(10):e877-e886. doi: 10.1212/WNL.0000000000005060. Epub 2018 Feb 2.


Objective: To evaluate whether amyloid-related imaging abnormalities with edema/effusion (ARIA-E) observed in bapineuzumab clinical trials was associated with specific biomarker patterns.

Methods: Bapineuzumab, an anti-β-amyloid monoclonal antibody, was evaluated in patients with mild to moderate Alzheimer disease. Amyloid PET imaging, CSF biomarkers, or volumetric MRI (vMRI) were assessed.

Results: A total of 1,512 participants underwent one or more biomarker assessments; 154 developed incident ARIA-E. No differences were observed at baseline between ARIA-E and non-ARIA-E participants in brain amyloid burden by PET, the majority of vMRI measures, or CSF biomarkers, with the exception of lower baseline CSF Aβ42 in APOE ε4 noncarrier ARIA-E vs non-ARIA-E groups (bapineuzumab non-ARIA-E p = 0.027; placebo non-ARIA-E p = 0.012). At week 71, bapineuzumab-treated participants with ARIA-E vs non-ARIA-E showed greater reduction in brain amyloid PET, greater reductions in CSF phosphorylated tau (p-tau) (all comparisons p < 0.01), and total tau (t-tau) (all comparisons p < 0.025), and greater hippocampal volume reduction and ventricular enlargement (all p < 0.05). Greater reduction in CSF Aβ40 concentrations was observed for ARIA-E versus both non-ARIA-E groups (bapineuzumab/placebo non-ARIA-E p = 0.015/0.049). No group differences were observed at week 71 for changes in whole brain volume or CSF Aβ42.

Conclusions: Baseline biomarkers largely do not predict risk for developing ARIA-E. ARIA-E was associated with significant longitudinal changes in several biomarkers, with larger reductions in amyloid PET and CSF p-tau and t-tau concentrations, and paradoxically greater hippocampal volume reduction and ventricular enlargement, suggesting that ARIA-E in bapineuzumab-treated cases may be related to increased Aβ efflux from the brain and affecting downstream pathogenic processes.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Aniline Compounds / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Apolipoproteins E / genetics
  • Biomarkers / cerebrospinal fluid*
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Female
  • Humans
  • Immunologic Factors / therapeutic use*
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Mental Status Schedule
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid
  • Positron-Emission Tomography
  • Thiazoles / pharmacokinetics
  • Treatment Outcome
  • tau Proteins / cerebrospinal fluid


  • 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
  • Amyloid beta-Peptides
  • Aniline Compounds
  • Antibodies, Monoclonal, Humanized
  • Apolipoproteins E
  • Biomarkers
  • Immunologic Factors
  • Peptide Fragments
  • Thiazoles
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins
  • bapineuzumab