Alzheimer's Disease-Modifying Therapy

For over two decades, the amyloid hypothesis — that accumulation of amyloid-beta plaques drives Alzheimer's disease — guided drug development despite repeated clinical failures. Dozens of anti-amyloid therapies failed to slow cognitive decline. The question was not just whether amyloid clearance was achievable, but whether removing it would actually help patients.

Aducanumab's EMERGE and ENGAGE trials (2021) produced contradictory results — one positive, one negative — leading to a controversial FDA accelerated approval and intense debate. Lecanemab's CLARITY AD trial (2023) provided the first unambiguous evidence: a 27% slowing of cognitive decline on CDR-SB over 18 months. Donanemab's TRAILBLAZER-ALZ 2 (2023) showed even larger effects in patients with low/medium tau burden, with 35% slowing of decline. These trials finally demonstrated that amyloid clearance could meaningfully slow Alzheimer's progression.

Lecanemab received traditional FDA approval in 2023, and donanemab in 2024. CMS agreed to cover anti-amyloid therapies for patients meeting trial criteria. The field rapidly developed consensus on ARIA (amyloid-related imaging abnormalities) monitoring, patient selection via amyloid PET or CSF biomarkers, and APOE4 genotyping for risk stratification.

Anti-amyloid antibodies represent the first disease-modifying therapies for Alzheimer's disease, though the clinical benefit (27-35% slowing) is modest and is weighed against the risk of ARIA (brain swelling and microhaemorrhages). Current research focuses on earlier intervention (pre-symptomatic treatment in at-risk individuals), combination approaches targeting tau alongside amyloid, and blood-based biomarkers to replace expensive PET scans and invasive lumbar punctures for diagnosis.