Alzheimer’s disease is a complex neurodegenerative condition that progressively erodes memory, thinking, and behavior. It is characterized by abnormal protein accumulation in the brain, leading to neuronal damage and cognitive decline. While a cure remains elusive, monoclonal antibodies represent a therapeutic strategy addressing the disease’s underlying biological processes.
How Monoclonal Antibodies Target Alzheimer’s
The progression of Alzheimer’s disease is closely linked to two distinct protein abnormalities in the brain: amyloid-beta plaques and tau tangles. Amyloid-beta proteins can clump to form sticky plaques outside nerve cells, disrupting their function. Inside neurons, tau proteins can twist into abnormal, fiber-like strands called tangles, interfering with cellular transport and communication.
Monoclonal antibodies are laboratory-produced molecules that mimic the immune system’s ability to target specific substances. They are engineered to bind to amyloid-beta or tau proteins.
Once bound, these antibodies facilitate the clearance of abnormal proteins from the brain. This can involve promoting phagocytosis of amyloid-beta by microglia (the brain’s immune cells), activating the complement system to clear cellular debris, or directly dissolving amyloid-beta structures. By removing these protein aggregates, monoclonal antibodies aim to mitigate amyloid’s harmful effects and potentially slow cognitive decline.
Approved Monoclonal Antibody Treatments
Several monoclonal antibody drugs have received regulatory approval for the treatment of Alzheimer’s disease. Aducanumab, marketed as Aduhelm, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in June 2021. This antibody targets aggregated amyloid-beta, reducing brain amyloid-beta levels. Aducanumab is intended for patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease.
Lecanemab, known by the brand name Leqembi, received accelerated FDA approval in January 2023, followed by traditional approval in July 2023. This antibody targets soluble amyloid-beta protofibrils, which are neurotoxic aggregates. Lecanemab is indicated for individuals with early Alzheimer’s disease, specifically those with mild cognitive impairment or mild Alzheimer’s dementia, and confirmed amyloid pathology in the brain.
Donanemab, approved by the FDA in July 2024, is another monoclonal antibody targeting amyloid plaques. This drug clears aggregated amyloid-beta proteins that have already clumped together to form plaques. Donanemab is approved for adults with early symptomatic Alzheimer’s disease, which includes individuals with mild cognitive impairment and mild dementia, provided they have confirmed amyloid plaques. All three approved monoclonal antibodies are administered via intravenous infusion.
Treatment Effectiveness and Side Effects
Clinical trials for approved monoclonal antibodies have shown varying degrees of effectiveness in slowing cognitive decline and reducing amyloid plaques. Lecanemab, in its Phase 3 Clarity AD trial, demonstrated a statistically significant reduction in cognitive decline over 18 months in patients with early-stage Alzheimer’s. This medication also significantly reduced and, in some cases, cleared amyloid plaques in the brain.
For donanemab, a Phase 3 study showed a significant slowing of cognitive and functional decline in individuals with early symptomatic Alzheimer’s disease, with some analyses suggesting a 20-35% reduction in decline. Donanemab also significantly reduced amyloid plaque burden, with an average reduction of 84% at 18 months in trials.
Despite these benefits, these treatments are associated with specific side effects, with Amyloid-Related Imaging Abnormalities (ARIA) being the most notable. ARIA manifests as either ARIA-E, which involves temporary brain swelling or fluid accumulation (edema/effusion), or ARIA-H, which includes small brain bleeds (microhemorrhages) or superficial siderosis (iron deposits from previous bleeds). These abnormalities are detected through brain MRI scans.
In clinical trials, ARIA incidence varied among the antibodies. Aducanumab showed ARIA in approximately 41% of participants (ARIA-E in 35%, ARIA-H in 19%). Lecanemab had ARIA-E in 12.6% and ARIA-H in 17.3%. Donanemab treatment was linked to ARIA in 37% of participants (ARIA-E in 24.4%, ARIA-H in 31.3%).
Most ARIA-E cases were mild to moderate, often asymptomatic, and resolved. However, serious ARIA events are possible, including fatalities. The risk of ARIA is higher in individuals who carry the APOE ε4 gene allele.
Future Directions in Monoclonal Antibody Research
Research into monoclonal antibodies for Alzheimer’s disease continues to evolve, exploring avenues beyond current treatments. Scientists are investigating new targets in the complex pathology of Alzheimer’s, moving beyond just amyloid-beta and tau proteins. These efforts aim to address other contributing factors like neuroinflammation or synaptic dysfunction, which could offer additional therapeutic benefits.
Combination therapies are also a significant area of focus, recognizing that Alzheimer’s is a multifaceted disease likely requiring multiple approaches. Combining existing anti-amyloid antibodies with agents targeting other biological pathways, such as those involved in tau pathology or neuroinflammation, could potentially enhance treatment effects and further slow disease progression. Researchers are also exploring alternative delivery methods for these antibodies to improve brain penetration and reduce side effects, reflecting a dynamic and ongoing commitment to developing more effective and safer treatments.