What is the new breakthrough for Alzheimer's disease? Understanding anti-amyloid therapies

According to the Alzheimer's Association, over 6 million Americans are living with Alzheimer's disease. A recent and significant advance addressing this pervasive condition has been the approval of disease-modifying anti-amyloid therapies, representing a new breakthrough for Alzheimer's disease by targeting its underlying biology.

Quick Summary

The new breakthrough for Alzheimer's disease involves anti-amyloid monoclonal antibodies, such as donanemab (Kisunla) and lecanemab (Leqembi), which have received FDA approval to slow cognitive decline in patients with early-stage Alzheimer's by clearing beta-amyloid plaques from the brain.

Key Points

• FDA Approval: The FDA has approved two anti-amyloid therapies, donanemab (Kisunla) and lecanemab (Leqembi), that represent the newest breakthroughs for treating early-stage Alzheimer's disease.

• Disease-Modifying Treatment: Unlike older drugs that only address symptoms, these new therapies target and remove beta-amyloid plaques from the brain, which is one of the underlying causes of the disease.

• Eligibility Restrictions: These treatments are only for patients in the early stages of Alzheimer's disease (mild cognitive impairment or mild dementia) who have biomarker confirmation of amyloid plaques.

• Risks and Monitoring: Both treatments carry a risk of Amyloid-Related Imaging Abnormalities (ARIA), such as brain swelling and microhemorrhages, necessitating regular MRI scans for monitoring.

• Future Research: Research continues on other potential breakthroughs, including therapies that target the tau protein, improve brain metabolism, or use novel lithium compounds.

• Availability and Cost: The high cost and strict eligibility criteria for these infusions present significant challenges for broad availability and insurance coverage.

A New Era of Alzheimer's Treatment

For decades, Alzheimer's disease treatments were limited to managing symptoms. That has changed with the arrival of a new class of therapies: disease-modifying anti-amyloid monoclonal antibodies. These treatments represent a paradigm shift by addressing one of the core pathologies of the disease—the accumulation of beta-amyloid plaques in the brain. This marks the first time that FDA-approved drugs can actually slow, rather than merely mask, the progression of Alzheimer's in its early stages. The approval of these therapies opens a new chapter in the fight against a disease that profoundly impacts millions of individuals and their families.

The Science Behind Anti-Amyloid Therapies

At the heart of this breakthrough is the immune-based approach of using monoclonal antibodies. These are laboratory-created antibodies designed to target and clear specific substances in the body. In the case of Alzheimer's, these therapies are engineered to bind to beta-amyloid, a protein fragment that aggregates to form toxic plaques in the brains of people with the disease. By tagging these plaques for removal by the body's own immune system, the therapies aim to mitigate the neuronal damage that drives cognitive decline.

Donanemab (Kisunla)

Approved by the FDA in July 2024, donanemab (brand name Kisunla) is a prominent example of this new therapy class. It is administered via an intravenous infusion every four weeks and is intended for patients with early symptomatic Alzheimer's who have confirmed amyloid plaques.

Key aspects of donanemab include:

• Targeted clearance: The drug is designed to specifically target the pyroglutamate-modified forms of beta-amyloid found on mature plaques.
• Reduced amyloid burden: Clinical trials have demonstrated significant reduction of amyloid plaques, with some patients achieving low enough levels to potentially consider stopping treatment.
• Slowing decline: Trial results showed a reduction in cognitive and functional decline in patients with early-stage disease.
• Monitoring: Patients require regular brain MRI scans to monitor for a common side effect known as Amyloid-Related Imaging Abnormalities (ARIA), which includes brain swelling and bleeding.

Lecanemab (Leqembi)

Lecanemab (brand name Leqembi), another anti-amyloid therapy, received full FDA approval in July 2023. It works by targeting and removing soluble amyloid-beta protofibrils, an early-stage form of the plaque-forming protein.

Key details of lecanemab include:

• Administration: The drug is also given as an intravenous infusion, typically every two weeks, though a less frequent maintenance dose has also been approved.
• Efficacy: Trials showed it moderately slowed cognitive and functional decline over 18 months in people with early Alzheimer's.
• Side effects: Similar to donanemab, lecanemab also carries a risk of ARIA, as well as infusion-related reactions.

Comparison of Donanemab and Lecanemab

While both therapies aim to clear amyloid plaques, there are key differences in their administration, specific targets, and clinical trial results.

Feature	Donanemab (Kisunla)	Lecanemab (Leqembi)
Mechanism	Targets and removes established amyloid plaques.	Targets and removes soluble beta-amyloid protofibrils.
Frequency	Monthly intravenous infusion.	Bi-weekly (every two weeks) or monthly maintenance dose.
Dosing Schedule	Fixed duration; treatment can potentially be stopped once plaque clearance is achieved.	Continuous treatment unless discontinued for other reasons.
Effect on Decline	Slowed decline by up to 35% at 18 months in early-stage patients.	Moderately slowed decline over 18 months in early-stage patients.
Side Effects (ARIA)	Risk of brain swelling and bleeding, requiring regular MRI monitoring.	Risk of brain swelling and bleeding, requiring regular MRI monitoring.
Cost	Priced at $32,000 per year.	Priced at $26,500 per year.

Challenges and Considerations

While these advancements are a cause for optimism, they are not without challenges.

1. Strict Eligibility: These therapies are only indicated for individuals with early-stage Alzheimer's disease who have biomarker confirmation of amyloid plaques. This excludes many people with more advanced disease.
2. Access and Affordability: The high annual cost of treatment and the resources needed for frequent infusions and monitoring can be significant hurdles. In the U.S., coverage by Medicare and private insurers depends on specific patient criteria.
3. Safety Concerns: The risk of ARIA, particularly for those with the APOE ε4 gene variant, necessitates careful monitoring and shared decision-making between patients, caregivers, and clinicians.

The Future of Alzheimer's Research

Looking beyond the current therapies, the scientific community continues to explore new frontiers. Researchers are investigating other potential treatment avenues, including:

• Tau Protein Targeting: Focusing on the tau protein, another hallmark of Alzheimer's that forms tangles inside brain cells.
• Metabolic Pathways: Exploring drugs that improve brain metabolism, potentially slowing disease progression.
• Lithium Compounds: Novel lithium-based compounds are being studied for their ability to protect against Alzheimer's pathology in preclinical models.
• Blood Biomarkers: The development of blood-based biomarkers is advancing rapidly, offering a less invasive way to detect amyloid and monitor treatment response.

Conclusion

The approval of anti-amyloid therapies like donanemab and lecanemab represents a profound shift in how Alzheimer's disease is treated. By moving from purely symptomatic management to disease-modifying strategies, these breakthroughs offer new hope for slowing progression in early-stage patients. However, these developments also highlight the complexities of treatment, emphasizing the need for careful patient selection, monitoring, and continued investment in research to develop even more effective and accessible therapies for the future.

For more information on navigating the complexities of Alzheimer's treatment, visit the Alzheimer's Association website: https://www.alz.org.

Frequently Asked Questions

What is the new breakthrough for Alzheimer's disease?

The newest breakthrough for Alzheimer's is the FDA approval of disease-modifying anti-amyloid therapies, including donanemab (Kisunla) and lecanemab (Leqembi), which are the first treatments to address the underlying pathology of the disease.

How do donanemab and lecanemab work?

These drugs work by using monoclonal antibodies to target and help clear the beta-amyloid plaques that accumulate in the brains of people with Alzheimer's disease, thereby slowing cognitive decline.

Who is eligible for the new Alzheimer's treatments?

Eligibility is limited to individuals with early symptomatic Alzheimer's disease (mild cognitive impairment or mild dementia) who have confirmed elevated levels of beta-amyloid in their brain.

What are the potential side effects of anti-amyloid therapies?

A common side effect is Amyloid-Related Imaging Abnormalities (ARIA), which can involve brain swelling and bleeding. Patients are carefully monitored with regular MRI scans to detect and manage this risk.

Are these new Alzheimer's treatments a cure?

No, these treatments are not a cure. They are disease-modifying therapies that can slow the progression of cognitive and functional decline in the early stages of the disease, but they cannot reverse or stop it completely.

Is the APOE ε4 gene variant important for these treatments?

Yes, carrying the APOE ε4 gene variant is associated with a higher risk of ARIA, the main side effect. The FDA recommends genetic testing for this variant before treatment to inform risk-benefit discussions.

What happens when amyloid is cleared from the brain?

For donanemab, clinical trials showed that treatment could be stopped once amyloid plaque levels dropped sufficiently, though the long-term impact on re-accumulation is still being studied. For lecanemab, treatment is typically continued.