The New Era of Alzheimer's Treatment
For decades, treatments for Alzheimer’s disease focused primarily on managing symptoms, not altering the underlying disease progression. However, the last few years have marked a significant shift with the development and FDA approval of disease-modifying therapies. These new medications represent a monumental step forward by targeting the brain's accumulation of amyloid-beta (Aβ) plaques, a hallmark of Alzheimer's pathology. This innovative class of drugs offers hope for slowing down cognitive decline in patients with early-stage Alzheimer's and mild cognitive impairment (MCI).
Leqembi (Lecanemab): Targeting Soluble Amyloid Protofibrils
Leqembi (lecanemab), co-developed by Eisai and Biogen, was the first anti-amyloid medication to receive full traditional FDA approval in July 2023, followed by approval for a weekly subcutaneous maintenance injection in August 2025.
How it Works
Leqembi is a monoclonal antibody that targets and binds to soluble amyloid-beta (Aβ) protofibrils. Protofibrils are small, toxic aggregates that precede the formation of larger, insoluble amyloid plaques. By targeting these smaller, neurotoxic aggregates, Leqembi helps the immune system clear them from the brain, preventing their toxic effects and reducing the overall amyloid burden.
Administration and Efficacy
- Initial Infusion Phase: Patients begin with intravenous (IV) infusions every two weeks at an infusion center.
- Maintenance Phase: After completing the initial IV phase and achieving a certain level of plaque clearance, patients can transition to a weekly at-home, subcutaneous autoinjector. In the Phase 3 CLARITY-AD trial, Leqembi demonstrated a statistically significant slowing of cognitive and functional decline by approximately 27% over 18 months in individuals with early Alzheimer's disease compared to placebo.
Kisunla (Donanemab): Clearing Established Amyloid Plaques
Kisunla (donanemab-azbt), developed by Eli Lilly, received traditional FDA approval in July 2024 for the treatment of early-stage Alzheimer’s disease.
How it Works
Kisunla is another monoclonal antibody that targets and clears amyloid plaques from the brain, but it works differently from Leqembi. Donanemab specifically targets a modified form of amyloid-beta that is present in established, larger amyloid plaques. This unique mechanism allows it to facilitate the removal of pre-existing plaques. A key aspect of Donanemab's clinical trial design was a “treat to clearance” approach, where treatment could be stopped once a patient’s brain amyloid was reduced to a certain level.
Administration and Efficacy
Kisunla is administered via intravenous infusion every four weeks. In the Phase 3 TRAILBLAZER-ALZ 2 study, donanemab was found to slow clinical decline by up to 35% in patients with early symptomatic Alzheimer's disease who had low-to-medium levels of tau protein.
Understanding the Risks: Amyloid-Related Imaging Abnormalities (ARIA)
Both Leqembi and Kisunla carry a boxed warning for the risk of Amyloid-Related Imaging Abnormalities (ARIA). ARIA is a common side effect of this class of anti-amyloid therapies and can manifest in two forms:
- ARIA-E (Edema): Temporary brain swelling or fluid accumulation.
- ARIA-H (Hemorrhage): Small spots of bleeding (microhemorrhages) or larger hemorrhages in or on the brain's surface.
While most ARIA cases are asymptomatic and resolve over time, serious and life-threatening events can occur, especially in individuals with a specific genetic risk factor. Patients who are APOE ε4 homozygotes have a significantly higher risk of experiencing ARIA. For this reason, genetic testing for ApoE4 is recommended before starting treatment to inform the risk-benefit discussion, and frequent MRI scans are required to monitor for ARIA.
Comparing Leqembi and Kisunla
Choosing between Leqembi and Kisunla depends on individual patient factors and requires a detailed discussion with a healthcare provider. The primary differences lie in their mechanism of action, administration frequency, and the specific trial results.
| Feature | Leqembi (Lecanemab) | Kisunla (Donanemab) |
|---|---|---|
| Mechanism of Action | Targets soluble Aβ protofibrils | Targets established Aβ plaques |
| Administration | Biweekly IV infusion initially; weekly subcutaneous maintenance | Monthly IV infusion until plaque clearance |
| Efficacy | Slowed decline by ~27% over 18 months | Slowed decline by up to 35% in early-stage patients |
| Treatment Duration | Ongoing treatment to sustain plaque removal | Can be discontinued once plaques are cleared |
| ARIA Risk | Risk of ARIA-E and ARIA-H, lower rate than Donanemab trials | Risk of ARIA-E and ARIA-H, potentially higher rate in trials |
The Outlook on Future and Emerging Treatments
The landscape of Alzheimer's treatment is evolving rapidly. The approval of Leqembi and Kisunla validates the anti-amyloid approach and opens the door for further innovation. Researchers are now focusing on:
- Alternative Delivery: The subcutaneous autoinjector for Leqembi is a prime example of improving convenience and access. Other options are being explored for current and future therapies.
- Combination Therapies: Given that Alzheimer's is a complex disease, future strategies may involve combining different treatments to target both amyloid and other pathologies, such as tau tangles and neuroinflammation.
- Novel Targets: The development of medications targeting tau protein, which forms tangles inside neurons, is a major area of research. Experimental tau vaccines are also in development.
- Oral Medications: An oral anti-amyloid medication, ALZ-801, is in Phase 3 trials, potentially offering a pill-based treatment option.
Conclusion: A Step Forward in the Fight Against Cognitive Decline
The approval of Leqembi and Kisunla represents a historic breakthrough, offering the first medications that can actively slow the progression of early-stage Alzheimer’s disease. While not a cure, they provide a meaningful delay in cognitive and functional decline, offering patients and their families more time and better quality of life. The future of treatment is moving toward more convenient administration, individualized therapy based on patient genetics and biomarkers, and combination approaches addressing the full spectrum of the disease. This new era of disease-modifying therapies is paving the way for more effective solutions against cognitive decline. For more information on Alzheimer's treatments and clinical research, consult your healthcare provider and authoritative sources like the National Institute on Aging.
