Amyloid Plaque-Lowering Monoclonal Antibodies
The class of drugs used for dissolving amyloid plaque in Alzheimer's disease is called anti-amyloid monoclonal antibodies (MABs), which are Aβ-directed plaque-lowering agents that work by activating microglia to engulf and remove amyloid-beta protein fibrillar plaques from the brain. 1, 2
Mechanism of Action
Anti-amyloid monoclonal antibodies are administered intravenously and, once in the brain, they activate microglia to engulf amyloid-beta protein fibrillar plaques, leading to dose-dependent reduction in cerebral amyloid burden 2, 3. These agents target different conformational features of amyloid-beta, including fibrillar, protofibrillar, and plaque forms, distinguishing them from failed first-generation antibodies that targeted non-toxic monomeric Aβ 3.
Currently Available Agents
FDA-Approved Therapies
Lecanemab (Leqembi) received traditional FDA approval in July 2023 and is administered through biweekly IV infusions for ongoing therapy 1, 4
Donanemab (Kisunla) received FDA approval in July 2024 and is administered as 700mg IV every 4 weeks for 3 doses, then 1400mg every 4 weeks, with the unique advantage of potential treatment cessation once amyloid clearance is achieved 1, 4
Aducanumab (Aduhelm) received accelerated FDA approval in June 2021 but has been discontinued from development and sale due to limited CMS reimbursement and acceptance 1, 5
Clinical Efficacy
Both lecanemab and donanemab demonstrate approximately 30% slowing of cognitive decline in early Alzheimer's disease over 18-month trials 4, 2. Donanemab achieves more rapid amyloid reduction (60-85 Centiloid units) compared to lecanemab, and reductions below a threshold of 15-25 Centiloids are associated with clinical benefit 4, 2.
Classification as Second-Generation Agents
These are classified as second-generation anti-amyloid MABs because they target pathogenic Aβ species and aggregates rather than non-toxic monomeric forms, which explains their clinical success compared to first-generation agents like solanezumab, bapineuzumab, and crenezumab that failed in clinical trials 3.
Disease-Modifying Mechanism
Anti-amyloid MABs represent the first disease-modifying therapies for Alzheimer's disease that achieve slowing of clinical decline by intervening in the basic biological processes of the disease, supporting the amyloid hypothesis as a valid therapeutic target 6. These are breakthrough agents that can slow the inevitable progression of AD into more severe cognitive impairment 6.