From the Guidelines
Monoclonal antibodies for Alzheimer's disease work by targeting and removing amyloid plaques or tau proteins that accumulate in the brain, with FDA-approved treatments including lecanemab and aducanumab, which bind to amyloid beta plaques and facilitate their clearance from brain tissue 1. These medications are administered as intravenous infusions, typically every two to four weeks in specialized infusion centers. The treatment process involves:
- Lecanemab given at 10 mg/kg every two weeks
- Aducanumab dosing starts lower and gradually increases to 10 mg/kg Treatment is generally intended for patients with mild cognitive impairment or early Alzheimer's disease who have confirmed amyloid pathology through PET scans or cerebrospinal fluid testing. These antibodies work through immunological mechanisms - after binding to amyloid plaques, they trigger microglial cells (the brain's immune cells) to engulf and clear the plaques. While these treatments can reduce amyloid burden, patients require regular monitoring with MRI scans due to potential side effects including ARIA (Amyloid-Related Imaging Abnormalities), which can cause brain swelling or small hemorrhages 1. The development of blood-based biomarkers has been hindered by the extreme complexity of the blood proteome, low biomarker abundance, and signal dilution from peripheral tissues, but significant advances have been achieved in the past decade, benefiting partly from the development of ultra-sensitive immunoassays and high-performance mass spectrometry technology platforms 1. Key points to consider:
- Blood-based biomarkers with high potential of providing accurate assessment of the AT(N) criteria include the Aβ42/40 ratio for amyloid pathology, phosphorylated tau (p-tau) for tau pathology, and neurofilament light-chain (NfL) and brain-derived tau for neurodegeneration/axonal injury
- The anticipated next stage in the development of highly sensitive and specific blood biomarkers for AD is to employ them in real-world settings for clinical diagnosis, population studies, and eligibility screening for therapeutic trials
- A major challenge facing the field is the need for increased standardization of collection, processing, and storage procedures, as well as agreed-upon procedures to monitor and maintain long-term stability in the biomarker measurements.
From the Research
Mechanism of Action
- Monoclonal antibodies, such as aducanumab, lecanemab, and donanemab, work by selectively binding to amyloid aggregates in both the oligomeric and fibrillar states, reducing beta-amyloid plaques and reestablishing neuronal calcium permeability 2, 3, 4.
- These antibodies activate microglia to engulf amyloid-beta protein fibrillar plaques, leading to a decrease in amyloid plaque burden 3.
- By targeting amyloid-beta, monoclonal antibodies can slow cognitive and functional decline in patients with early Alzheimer's disease, with approximately 30% reduction in decline over 18 months 3.
Types of Monoclonal Antibodies
- Aducanumab is a human monoclonal antibody that preferentially binds to aggregated amyloid-β, reducing the number of amyloid plaques and slowing disease progression 2, 5.
- Lecanemab has a high affinity for large and soluble Aβ protofibrils, and has shown a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs) in phase 2 clinical trials 4.
- Donanemab is another anti-amyloid monoclonal antibody that has been approved for the treatment of Alzheimer's disease, although less information is available on its specific mechanism of action 3.
Clinical Benefits and Risks
- Monoclonal antibodies have been shown to slow clinical decline and reduce amyloid plaque burden, providing hope for patients with Alzheimer's disease 2, 3, 6.
- However, these agents can also cause side effects, including amyloid-related imaging abnormalities (ARIA) and infusion reactions, which must be closely monitored during treatment initiation 3, 6.
- The success of monoclonal antibodies in treating Alzheimer's disease has fostered the development of more anti-amyloid therapies and new approaches to therapies for neurodegenerative disorders 6.