The Transition to Disease-Modifying Treatments

For decades, Alzheimer's disease (AD) treatment centered on symptomatic relief through medications like donepezil, galantamine, rivastigmine, and memantine. These drugs, introduced in the late 1990s and early 2000s, improve memory, attention, and daily functioning but do not alter the underlying disease process. Recognizing this limitation, researchers sought therapies addressing the root cause of AD, leading to the development of disease-modifying treatments like lecanemab (Leqembi).

Lecanemab, FDA-approved in January 2023 and insurance-covered since mid-2023, is the first therapy to slow disease progression by targeting early amyloid plaque accumulation in the brain. Unlike traditional therapies, which manage symptoms, lecanemab is the first true disease-modifying therapy for Alzheimer's disease that modifies the disease's biology, offering the potential to delay cognitive decline when treatment begins early.

How Lecanemab Works

Lecanemab is a monoclonal antibody-a lab-created antibody designed to specifically recognize and bind to the amyloid plaques that form early in Alzheimer's. It's administered as an intravenous infusion twice a month for 18 months, with the goal of enhancing the brain's ability to clear amyloid plaques effectively. Amyloid plaques are misfolded proteins that aggregate between neurons and disrupt normal brain function. By directly targeting these plaques, lecanemab aims to reduce their accumulation before it causes irreversible neuronal damage. The mechanism also decreases associated neurodegenerative biomarkers, such as phosphorylated tau and neuroinflammatory markers. Early intervention is key, as plaques take years to accumulate to levels that cause cognitive and functional decline.

Clinical Evidence and Predictive Factors

The Clarity AD trial provided valuable insights into lecanemab's efficacy over an 18-month period, comparing it with a placebo. The study focused on whether reducing amyloid plaques would slow cognitive and functional decline. Results were promising: lecanemab significantly reduced amyloid levels in the brain, and this was associated with a 30% slowing in the rate of functional decline across participants. However, individual responses varied, with some patients responding much better than others.

• Amyloid Reduction: Significant reduction in brain amyloid levels.
• Functional Outcomes: An approximate 30% slower rate of decline in cognitive and functional measures.
• Predictive Factors: Patients with mild cognitive impairment (MCI) experienced better outcomes than those with moderate dementia, emphasizing the importance of early intervention.
• Biomarker Correlation: Lower levels of tau, a marker of neuronal damage, predict better responses to treatment.

These findings highlight lecanemab's potential as a disease-modifying therapy, particularly when started in the earliest stages of AD.

One crucial finding from the trial is that earlier intervention appears to produce the best outcomes. Participants who began treatment with mild cognitive impairment, rather than moderate dementia, experienced slower disease progression and maintained functional abilities better both during the trial and at a follow-up two years later. This responsiveness aligns with tau protein levels, another biomarker of Alzheimer's burden. Tau proteins, which stabilize neuronal structures, become elevated as neurons are damaged. Your current tau levels, which are slightly above the normal range but still low, suggest a promising response to lecanemab, further supporting the benefit of starting therapy early in the disease process.

Side Effects and Considerations

Since lecanemab's introduction, it has generally been well-tolerated among patients. Common side effects observed in trials include mild infusion-related reactions, such as slight allergic responses. These are usually managed with a small dose of steroids and antihistamines given during treatment, with many patients reporting more side effects from the antihistamines than from the infusion itself. Another side effect, mild headaches, is also common and responds well to over-the-counter medications like Tylenol or gabapentin.

A more significant consideration with lecanemab is a side effect known as ARIA (amyloid-related imaging abnormalities), which can occur when amyloid plaques are rapidly cleared from the brain. ARIA has two types: ARIA-E, involving mild brain edema (swelling), and ARIA-H, which involves small brain microbleeds. The presence of ARIA-E in the Clarity AD trial was approximately 12.5%, often asymptomatic, or presenting with mild symptoms like slight headaches or dizziness, which resolved within one to two months without further intervention.

ARIA-H, or microbleeding, was observed in about 17.5% of participants, but notably, approximately 10% of those in the placebo group-who did not receive the medication-also experienced microbleeds. This phenomenon is likely due to cerebral amyloid angiopathy (CAA), a condition common in Alzheimer's in which amyloid plaques form around blood vessels, causing them to become brittle. This makes individuals with Alzheimer's predisposed to spontaneous microbleeds, with or without lecanemab. To reduce risk, we avoid prescribing lecanemab to patients with pre-existing microbleeds, identified through an MRI scan.

Personal Risk Assessment

Careful patient selection and monitoring optimize safety and efficacy.

• MRI Screening: Excludes patients with pre-existing microbleeds or major vascular damage, reducing ARIA risk.
• Genetic Testing: Identifies APOE genotype to assess ARIA likelihood.
• Individualized Management: Adjustments, such as pausing anticoagulants, further reduce bleeding risks.

Patients with mild symptoms, low tau levels, and favorable genetic profiles are ideal candidates for lecanemab.

Challenges and Future Directions

Despite its promise, lecanemab faces challenges:

• Access: High costs, specialized infusion facilities, and MRI monitoring may limit availability.
• Safety Profile: Long-term effects of ARIA and overall treatment safety require further study.
• Efficacy Debate: While benefits are evident, some experts question the clinical significance of observed improvements.

These considerations highlight the need for continued research, infrastructure development, and cost management to maximize lecanemab's impact.

Conclusion and Treatment Plan

Lecanemab represents a transformative step in Alzheimer's care, moving from symptomatic management to modifying the disease's trajectory. By addressing the underlying biology of AD, it offers patients the potential for prolonged cognitive stability and an improved quality of life. 

For individuals in early disease stages, lecanemab provides hope and a window of opportunity to slow progression, reinforcing the importance of early detection and personalized treatment strategies. Early amyloid targeting is critical, as plaques accumulate years before symptomatic AD. Patients initiating treatment during MCI or early-stage AD demonstrate the greatest benefit, maintaining cognitive and functional abilities longer than those starting later. This underscores the importance of early diagnosis and intervention for optimal outcomes.