Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients

J Alzheimers Dis. 2017;57(2):557-573. doi: 10.3233/JAD-160216.


Background: Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]).

Objectives: To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers).

Methods: Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described.

Results: In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo.

Conclusion: ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

Trial registration: ClinicalTrials.gov NCT00574132 NCT00575055.

Keywords: Alzheimer’s disease; NCT00575055 (Bapineuzumab-302); bapineuzumab; brain amyloid-related imaging abnormality; magnetic resonance imaging Registration: NCT00574132 (Bapineuzumab-301).

Publication types

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

MeSH terms

  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics
  • Amyloid / drug effects
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Apolipoprotein E4 / genetics
  • Brain / diagnostic imaging*
  • Brain / drug effects*
  • Cerebral Hemorrhage / diagnostic imaging
  • Cerebral Hemorrhage / epidemiology
  • Cerebral Hemorrhage / genetics
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Heterozygote
  • Humans
  • Immunologic Factors / adverse effects
  • Immunologic Factors / therapeutic use*
  • Incidence
  • Kaplan-Meier Estimate
  • Magnetic Resonance Imaging
  • Prevalence
  • Risk Factors
  • Severity of Illness Index
  • White Matter / diagnostic imaging
  • White Matter / drug effects


  • Amyloid
  • Antibodies, Monoclonal, Humanized
  • Apolipoprotein E4
  • Immunologic Factors
  • bapineuzumab

Associated data

  • ClinicalTrials.gov/NCT00574132
  • ClinicalTrials.gov/NCT00575055