A New Era of Dementia Treatment: Moving Beyond Symptom Management
For decades, dementia care primarily focused on managing symptoms rather than addressing the underlying disease pathology. Treatments like cholinesterase inhibitors (e.g., donepezil) and glutamate regulators (e.g., memantine) have been used to help with cognitive symptoms in Alzheimer's disease, but they do not slow the disease's progression. The recent FDA approval of several new drugs, most notably lecanemab and donanemab, signifies a major breakthrough. These therapies target the biological root of Alzheimer's by clearing the amyloid-beta plaques that build up in the brain and disrupt neural communication. This shift from symptom relief to disease modification is creating unprecedented possibilities for improving the quality of life and independence for those with early-stage disease.
Lecanemab (Leqembi): An Overview
Lecanemab (brand name Leqembi), developed by Eisai and Biogen, was granted traditional FDA approval in July 2023 for the treatment of early Alzheimer’s disease. This was the first traditionally approved treatment demonstrated to address the underlying biology of Alzheimer's and change the course of the disease.
How Lecanemab Works
Lecanemab is a monoclonal antibody administered via an intravenous (IV) infusion every two weeks. Its mechanism involves targeting and neutralizing amyloid-beta protofibrils—small, toxic clumps that form before mature amyloid plaques—and clearing them from the brain. By doing so, it reduces the overall amyloid burden and slows the rate of cognitive decline in eligible patients.
Clinical Trial Findings
The Phase 3 CLARITY AD trial showed that over 18 months, lecanemab slowed cognitive and functional decline by 27% compared to a placebo. Critically, it also demonstrated a significant reduction in brain amyloid plaque levels. This effect could be more significant over longer treatment periods, and studies are ongoing to investigate its long-term benefits.
Donanemab (Kisunla): A Targeted Approach
Donanemab (brand name Kisunla), from Eli Lilly, received traditional FDA approval in July 2024. Like lecanemab, it is a monoclonal antibody that targets amyloid plaques. However, donanemab is designed to be potentially discontinued once amyloid clearance is achieved, unlike lecanemab which is intended for indefinite use.
How Donanemab Works
Donanemab is administered as a monthly IV infusion. It targets a specific modified form of amyloid-beta that has already clumped together into larger plaques, initiating their removal from the brain. This slightly different mechanism of action may explain some of the differences observed in clinical trials compared to lecanemab.
Clinical Trial Findings
Donanemab's TRAILBLAZER-ALZ 2 trial demonstrated a slowing of cognitive and functional decline by 29% in the overall trial population over 18 months. For a subgroup of patients in the earliest stages with low-to-medium levels of tau protein, this effect was even more pronounced, showing a 35% slowing of decline. Notably, nearly half of the participants receiving donanemab cleared their amyloid plaques within a year, allowing treatment to be stopped.
Potential Risks and Monitoring
Both lecanemab and donanemab are associated with a significant risk called Amyloid-Related Imaging Abnormalities (ARIA), which can manifest as temporary brain swelling (ARIA-E) or microhemorrhages (ARIA-H). While most ARIA is asymptomatic, some individuals may experience side effects such as headache, confusion, or dizziness. In rare cases, more serious complications, including larger bleeds or seizures, can occur and can even be fatal.
To manage this risk, doctors require:
- Baseline and periodic magnetic resonance imaging (MRI) scans to monitor for ARIA throughout treatment.
- Genetic testing for the APOE ε4 gene, which increases the risk of ARIA, especially for carriers of two copies.
- Exclusion of patients with certain conditions or medications, such as blood thinners, that heighten the risk of bleeding.
Choosing Between Lecanemab and Donanemab
Selecting the right therapy is a complex decision made in consultation with a healthcare provider. There are several factors to consider, including patient eligibility, treatment schedule, side effect profile, and treatment goals. The following table provides a high-level comparison.
| Feature | Lecanemab (Leqembi) | Donanemab (Kisunla) |
|---|---|---|
| Target | Amyloid-beta protofibrils (early clumps) | Existing amyloid-beta plaques |
| Administration | Bi-weekly IV infusion | Monthly IV infusion (can stop if plaques cleared) |
| Maintenance Dosing | Ongoing | Can be discontinued after clearance |
| Cognitive Decline Slowing (18 mo) | ~27% vs placebo | ~29% vs placebo (up to 35% in early-stage) |
| Common Side Effects | Infusion-related reactions, ARIA, headache | Infusion-related reactions, ARIA, headache |
| Monitoring | Periodic MRI scans, APOE ε4 testing recommended | Periodic MRI scans, APOE ε4 testing recommended |
It is important to note that these drugs are not cures and have demonstrated only a modest slowing of decline over 18 months. They are most effective in the very early stages of the disease, underscoring the importance of early diagnosis and eligibility screening.
What the Future Holds
The approval of these new treatments is just the beginning. Researchers are actively exploring combination therapies that target multiple disease pathways, including both amyloid and tau proteins, similar to how HIV and cancer are treated. Efforts are also underway to develop more accessible forms of treatment, such as oral medications. Clinical trials are exploring whether these drugs can prevent Alzheimer's in people at high risk before symptoms even appear. A deeper understanding of the disease's complexities, combined with ongoing research, promises further innovation in the years ahead.
Consulting reputable health authorities is crucial for staying informed about the latest developments and understanding complex medical information. For more information on Alzheimer's disease research and treatment, visit the Alzheimer's Association website.
Conclusion
The introduction of lecanemab and donanemab represents a profound turning point in the fight against Alzheimer's disease. For the first time, patients with early-stage disease have access to disease-modifying therapies that can slow cognitive decline. While these drugs come with potential risks, they offer a promising new path forward and signal a new era of research and treatment. An informed discussion with a healthcare provider is the essential next step for any individual considering these groundbreaking options.
