Two comprehensive pharmacovigilance studies have provided new insights into the safety profiles of anti-amyloid monoclonal antibodies for Alzheimer's disease treatment, revealing significant differences between drugs and highlighting the importance of genetic screening in patient selection.
Comparative Safety Analysis Reveals Drug-Specific Risks
A real-world disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database examined 1,409 adverse drug events from lecanemab (892 cases) and aducanumab (517 cases) through Q2 2024. The study employed four signal detection algorithms and found that both drugs generated strong signals for amyloid-related imaging abnormalities (ARIA), cerebral microhemorrhage, and superficial siderosis of the central nervous system.
Notably, lecanemab demonstrated a significantly shorter median time-to-onset for adverse events compared to aducanumab (33 days versus 146 days). The analysis identified distinct adverse event profiles: lecanemab was uniquely associated with "brain fog," chills, and feeling cold, while aducanumab showed exclusive signals for cerebral infarction, posterior reversible encephalopathy syndrome, and concerning cancer signals including skin cancer and breast cancer.
Meta-Analysis Confirms Efficacy with Genetic Risk Stratification
A separate meta-analysis of five Phase III trials encompassing 4,824 patients (2,410 treatment, 2,414 control) provided robust evidence for the clinical benefits of lecanemab and donanemab in early Alzheimer's disease. The analysis demonstrated significant improvements across multiple cognitive measures: ADCOMS scores improved by 0.05 units, CDR-SB scores decreased by 0.49 units, and ADAS-Cog 14 scores showed a substantial reduction of 1.06 units compared to placebo.
The drugs achieved their primary mechanism of action, reducing amyloid burden on PET imaging by 72.99 SUVr units. However, this efficacy came with a substantial safety trade-off, as the overall ARIA risk increased 4.35-fold compared to placebo.
APOE ε4 Genotype Emerges as Critical Risk Factor
The meta-analysis revealed striking genetic associations with ARIA risk. ARIA-E (edema/effusion) risk increased 8.78-fold overall, but showed pronounced variation by APOE ε4 status. Non-carriers faced a 10.97-fold increased risk, while ε4 homozygotes experienced a 10.84-fold elevation. ARIA-H (hemosiderin deposits) risk increased 2.21-fold, with superficial siderosis showing higher risk (2.74-fold) than microhemorrhages (1.97-fold).
The pharmacovigilance study corroborated these findings, showing gender-specific differences in adverse event patterns. For lecanemab, male patients exclusively reported increased lacrimation, hiccups, and encephalitis, while female patients uniquely experienced formication, head injury, and subdural hematoma.
Clinical Implications for Treatment Selection
The research identified several previously unreported adverse events not included in current drug labels. For lecanemab, new signals included feeling cold, screaming, and encephalitis. For aducanumab, concerning signals emerged for skin cancer, breast cancer, and ischemic stroke, potentially related to immune function decline following amyloid-β removal.
The studies suggest that amyloid-β clearance may compromise immune function, as amyloid-β deposits play a positive role in immune response. The removal of these deposits by monoclonal antibodies could increase infection risk and potentially explain some of the observed adverse events.
Recommendations for Clinical Practice
Based on these findings, the researchers recommend implementing APOE ε4 genotyping as a standard pre-treatment assessment. APOE ε4 carriers, particularly homozygotes, should receive intensified MRI monitoring with baseline scans followed by monthly evaluations during the first three months of treatment.
The differential safety profiles suggest that drug selection should integrate patient preferences, genetic status, and healthcare resource accessibility. Lecanemab's gradual dose-escalation regimen may be preferable for older adults with heightened sensitivity to tolerability, while donanemab might align better with clinical scenarios requiring rapid biomarker improvements.
The studies emphasize that while these anti-amyloid therapies represent significant advances in disease-modifying treatment for Alzheimer's disease, their use requires careful risk-benefit assessment and individualized monitoring strategies. The identification of genetic risk factors and drug-specific adverse event profiles provides a foundation for precision medicine approaches in Alzheimer's disease treatment.
