Alzheimer's Imaging Consortium.

Area of Science:

• Neurology
• Neuroimaging
• Pharmacology

Background:

• Amyloid-related imaging abnormalities (ARIA-E) are a concern with amyloid-targeting therapies for Alzheimer's disease (AD).
• Key risk factors for ARIA-E include apolipoprotein E ε4 (APOE ε4) carrier status, microhemorrhages, and cerebral amyloid angiopathy (CAA).
• Distinguishing CAA from AD is challenging, as occipital amyloid plaque burden may be higher in CAA.

Purpose of the Study:

• To investigate the association between occipital amyloid burden and ARIA-E in participants with early symptomatic AD treated with donanemab.
• To determine if baseline occipital amyloid levels can predict the risk of ARIA-E.

Main Methods:

• Analysis of data from donanemab-treated participants in the TRAILBLAZER-ALZ, TRAILBLAZER-ALZ 2, and TRAILBLAZER-ALZ 4 studies.
• Amyloid pathology was assessed using florbetapir or florbetaben positron emission tomography (PET).
• Baseline occipital amyloid burden was calculated and compared to global amyloid assessments, with associations to ARIA-E analyzed using Cox proportional hazard modeling, adjusting for APOE ε4 status.

Main Results:

• A total of 2087 participants were analyzed, with varying levels of baseline occipital amyloid burden.
• Higher baseline occipital amyloid burden (comparable or elevated) was independently associated with a statistically significant increased risk of ARIA-E over 76 weeks.
• This association persisted even after accounting for APOE ε4 carrier status, and elevated occipital burden was linked to ARIA-E across all APOE ε4 carrier groups.

Conclusions:

• Elevated baseline occipital amyloid burden is significantly associated with an increased risk of ARIA-E in donanemab-treated early symptomatic AD patients.
• Occipital amyloid burden shows potential as a predictor for ARIA-E.
• Further validation using diverse methodologies and datasets is recommended to confirm these findings.