Among patients with early symptomatic Alzheimer disease, lower post-treatment amyloid levels following donanemab therapy were correlated with slower cognitive decline and reductions in Alzheimer-related plasma biomarkers over 76 weeks, according to a study published in JAMA Neurology.
In a phase 3 randomized controlled trial, 1,582 patients aged 60 to 85 years were assigned to receive intravenous donanemab or placebo every 4 weeks. Patients who achieved lower amyloid levels on positron emission tomography (PET) had smaller declines in scores on the integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Lower amyloid levels were also accompanied by greater decreases in plasma phosphorylated tau (p-tau217 and p-tau181) and glial fibrillary acidic protein (GFAP). No correlation was observed with neurofilament light chain (NfL).
At baseline, the mean amyloid level was approximately 103 Centiloids. Patients in the lowest post-treatment amyloid categories were almost entirely in the donanemab group, and all achieved amyloid clearance—defined as less than 24.1 Centiloids—by week 76.
Data were derived from the double-blind, placebo-controlled TRAILBLAZER-ALZ 2 trial, which enrolled patients with early symptomatic Alzheimer disease and confirmed amyloid and tau pathology. Donanemab was administered at 700 mg for the first three doses and 1,400 mg thereafter. The mean age was 73 years, and 57% were female. Amyloid plaque levels were quantified using PET imaging, and blood biomarkers were measured for p-tau217, p-tau181, GFAP, and NfL.
Patients were divided into ten groups based on their lowest observed post-treatment amyloid level. Researchers applied mixed-model repeated-measures analyses to estimate changes in cognition and biomarker outcomes and evaluated correlations between those changes and post-treatment amyloid levels.
"Analyzing post-treatment amyloid levels, rather than change from baseline, is a more appropriate approach," wrote Ming Lu, MD, of Eli Lilly and Company, Indianapolis, Indiana, and colleagues. This method more accurately reflects the post-treatment brain amyloid pathology by accounting for both baseline burden and subsequent reduction."
The researchers noted several limitations. The analysis was exploratory and posthoc. Grouping patients by their lowest observed amyloid value was not prespecified, which may limit reproducibility. No standardized method currently exists for classifying patients by post-treatment amyloid level. The population had relatively low representation of racial and ethnic minority populations. Multiplicity across comparisons was not adjusted for, and outcomes beyond 76 weeks were not assessed.
Researchers reported that the extent of amyloid reduction was associated with both clinical and biologic outcomes, supporting amyloid plaque removal as a therapeutic mechanism. The findings suggested that post-treatment amyloid levels may serve as a surrogate biomarker for treatment efficacy in amyloid-targeting therapies for early symptomatic Alzheimer disease.
Full disclosures can be found in the published study.
Source: JAMA Neurology
