The Shift from Symptom Management to Disease Modification
Historically, Alzheimer's medications focused on managing symptoms with limited impact on disease progression. Newer drugs like donepezil offered only temporary cognitive benefits. The recent FDA approvals of Lecanemab (Leqembi) and Donanemab (Kisunla) are a significant change, marking the first therapies to target the underlying pathology of Alzheimer's. This new approach aims to modify the disease's course, but understanding its true impact is essential.
Targeting the Underlying Cause: Beta-Amyloid
These new therapies operate on the principle that removing beta-amyloid plaques from the brain can slow disease progression. Beta-amyloid is a protein that accumulates in the brain in Alzheimer's patients, forming plaques years before symptoms appear. Lecanemab and Donanemab are monoclonal antibodies designed to clear these plaques.
Lecanemab (Leqembi): An Early Intervention
Approved in July 2023, Lecanemab is administered via IV infusion every two weeks, with a weekly subcutaneous option also available. {Link: Alzheimer's Society https://www.alzheimers.org.uk/blog/what-lecanemab} Clinical trials showed Lecanemab slowed cognitive and functional decline in early-stage Alzheimer's patients by about 27% over 18 months compared to placebo, helping them maintain independence longer.
Donanemab (Kisunla): A Plaque-Clearing Strategy
Donanemab, approved in July 2024, also targets amyloid plaques but specifically the pyroglutamate form found in established plaques. Administered monthly by IV infusion, Donanemab treatment can potentially stop once plaques are cleared, monitored by a PET scan. Trials demonstrated up to 29% slowing of cognitive and functional decline in early Alzheimer's, with greater benefits in patients with lower tau protein levels.
Understanding Efficacy: Why 'Miracle' is Misleading
The term "miracle drug" for therapies like Lecanemab and Donanemab can create unrealistic expectations. While their trial results are scientifically significant and offer hope, they are not a cure and do not restore lost cognitive function.
Key considerations for managing expectations:
- Modest Benefit: The observed slowing of decline is statistically significant but may be subtle for individuals. It is not a reversal or complete halt of the disease.
- Early-Stage Only: These therapies are only approved for those with mild cognitive impairment or mild dementia; they are not for moderate to severe dementia.
- Significant Risks: The drugs have potentially serious side effects, which must be carefully considered.
Potential Risks and Side Effects
The most significant side effect for both drugs is Amyloid-Related Imaging Abnormalities (ARIA), detectable by MRI. ARIA can include brain swelling (ARIA-E) and small bleeds (ARIA-H). While often without symptoms, ARIA can be serious or rarely life-threatening, requiring regular MRI monitoring. The risk is higher for individuals with the APOE4 gene variant. Other common side effects include infusion reactions, nausea, and headache. Patients should discuss these risks with their doctors.
Comparison of New Alzheimer's Medications
| Feature | Lecanemab (Leqembi) | Donanemab (Kisunla) |
|---|---|---|
| Mechanism | Binds to and clears amyloid protofibrils (early-stage aggregates). | Binds to and clears established amyloid plaques. |
| Administration | IV infusion every two weeks. Subcutaneous option also available. | IV infusion every four weeks. |
| Clinical Efficacy | Slowed decline by ~27% over 18 months in early-stage AD. | Slowed decline by ~29% over 18 months in early-stage AD (up to 35% in low-tau patients). |
| Stopping Criteria | No predefined stop date based on plaque clearance. | Treatment can be stopped once amyloid plaques are sufficiently cleared. |
| Primary Side Effect | ARIA (brain swelling and bleeding), infusion reactions. | ARIA (brain swelling and bleeding), infusion reactions. |
| Target Patient Stage | Early symptomatic Alzheimer's (MCI or mild dementia) with confirmed amyloid. | Early symptomatic Alzheimer's (MCI or mild dementia) with confirmed amyloid. |
The Future of Dementia Treatment
Beyond anti-amyloid therapies, the future of dementia treatment is exploring multiple avenues, including targeting tau protein, inhibiting inflammation, protecting brain cells, and exploring combination approaches. Prevention trials are also underway. {Link: Alzheimer's Society https://www.alzheimers.org.uk/blog/what-lecanemab}
Conclusion: Hope in Progress, Not in a Cure
The approval of Lecanemab and Donanemab is a historic breakthrough in Alzheimer's treatment, demonstrating the possibility of slowing progression by targeting underlying biology. These therapies are not a cure and have serious risks but offer potential benefits for eligible patients. The future of dementia care involves these new medications, continued research, and holistic patient support {Link: Alzheimer's Society https://www.alzheimers.org.uk/blog/what-lecanemab}.
For further information, consult a healthcare provider or resources like the Alzheimer's Association.
Key Research and Breakthroughs
Key research includes the release of guidelines for using blood tests for earlier diagnosis, confirmation that lifestyle changes can improve cognition in at-risk older adults, and suggestions that existing medications for conditions like blood pressure and diabetes might slow cognitive decline. Early real-world studies of Lecanemab and Donanemab show safety profiles comparable to or better than trials. Trials are also testing Semaglutide for its potential to reduce neuroinflammation {Link: Alzheimer's Society https://www.alzheimers.org.uk/blog/what-lecanemab}.
A Note on Other Dementias
Lecanemab and Donanemab are specifically for Alzheimer's disease, the most common form of dementia {Link: Alzheimer's Society https://www.alzheimers.org.uk/blog/what-lecanemab}. They are not treatments for other types like vascular, Lewy body, or frontotemporal dementia, for which research continues on different paths.
