The year 2025 witnessed the consolidation of anti-amyloid monoclonal antibodies as disease-modifying therapies for early Alzheimer's disease, with lecanemab and donanemab receiving widespread regulatory approvals and entering clinical practice [1][2][3][4][5].
The TRAILBLAZER-ALZ 2 trial demonstrated that donanemab significantly slowed clinical progression at 76 weeks in participants with early symptomatic Alzheimer's disease and amyloid-tau pathology, achieving 28.9% slowing of decline in the combined low/medium and high tau population [1]. Mechanistic studies revealed that lecanemab preferentially binds to smaller, early-stage amyloid-beta aggregates present in early disease, whereas gantenerumab and aducanumab showed preference for fibrillar aggregates, potentially explaining lecanemab's superior therapeutic performance [2].
Treatment paradigms shifted toward early diagnosis and biomarker-guided intervention, emphasizing amyloid PET imaging and plasma phosphorylated tau (p-tau) measurements for patient selection [3][4]. However, controversy persisted regarding the modest clinical benefits (equivalent to approximately 3-6 months of disease progression delay), significant costs, and risks of amyloid-related imaging abnormalities (ARIA) including cerebral edema and microhemorrhages [5]. The pipeline expanded to include combination therapies targeting both amyloid and tau pathology, with add-on therapeutic strategies under active investigation [3].
Why it matters:
For clinicians: Anti-amyloid antibodies represent the first FDA-approved disease-modifying therapies for Alzheimer's disease, fundamentally changing practice from purely symptomatic management to targeting underlying pathology. Patient selection requires sophisticated biomarker assessment including amyloid PET or CSF analysis and baseline MRI to exclude ARIA risk factors. Monitoring protocols must include serial MRI to detect ARIA, particularly in APOE4 carriers who face higher risk. The modest clinical benefit must be weighed against infusion burden, monitoring requirements, ARIA risks, and substantial costs.
For researchers: The success of anti-amyloid therapy validates the amyloid hypothesis while highlighting that amyloid removal alone provides only modest clinical benefit. Future research must focus on combination therapies targeting multiple pathological mechanisms (tau, neuroinflammation, synaptic dysfunction), earlier intervention in preclinical stages, biomarker-driven patient selection beyond amyloid positivity, and strategies to enhance efficacy while minimizing ARIA risk.
References
- Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527. doi: 10.1001/jama.2023.13239
PubMed: https://pubmed.ncbi.nlm.nih.gov/37459141/ - Bešić E, Finzel S, Walti K, et al. Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease. Alzheimers Dement. 2025. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/40237235/ - Cummings JL, Apostolova LG, Rabinovici GD, et al. Add-on combination therapy with monoclonal antibodies: Implications for drug development. Alzheimers Dement. 2025. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/41145338/ - Wang CY, Liu CY, Tai CT, et al. A 2025 update on treatment strategies for the Alzheimer's disease spectrum. J Chin Med Assoc. 2025;88(7). [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/40442885/ - Perry G, Nunomura A, Pappolla MA, et al. Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit. J Prev Alzheimers Dis. 2024. [Epub ahead of print]
PubMed: https://pubmed.ncbi.nlm.nih.gov/38830549/