Background
In Alzheimer’s disease, the accumulation and aggregation of amyloid beta (Aβ) peptide into extracellular amyloid plaques is an early event that precedes neurodegeneration and functional and cognitive impairment. Genetic variants are also involved in the onset of AD. Apolipoprotein E may interact with responses to amyloid targeting therapies.
Methods
- Aggregate data from trials enrolling patients with amyloid-positive, early symptomatic Alzheimer’s disease were examined for disease progression.
- Trials testing antibody-based therapeutics for which the population was fully characterized for amyloid pathology and efficacy data by APOE ε4 status were included.
- To evaluate the rate of progression of clinical decline in trials of amyloid-positive participants with early symptomatic AD by APOE ε4 status, data from placebo clinical trials were evaluated.
Results
- Pooled analysis of potentially effectual antibodies lecanemab, aducanumab, donanemab, and solanezumab shows slightly better efficacy in APOE ε4 carriers than in no carriers.
- Carrier and non-carrier mean differences from placebo using the Clinical Dementia Rating Scale-Sum of boxes were -0.30 and -0.20, and the AD Assessment Scale-Cognitive subscale values were -1.01 and -0.80.
- The decline in the APOE ε4 non-carrier placebo group was equal to or greater than that in carriers across multiple scales.
- The possibility of study success increases as the representation of the carrier population increases.
Conclusion
The result of this study suggests that APOE ε4 carriers have the same or better response than non-carriers to amyloid-targeting therapies and equal or less disease progression with placebo in amyloid-positive trials.