How can the effectiveness of 18 months of intravenous lecanemab (anti-amyloid therapy) be monitored in the absence of a pre-treatment PET (Positron Emission Tomography) amyloid scan, and can plasma p-tau 217 levels be used as a monitoring tool?

Monitoring Lecanemab Effectiveness Without Baseline Amyloid PET

Without a baseline amyloid PET scan, monitoring the effectiveness of lecanemab after 18 months is severely limited, and plasma p-tau 217 alone cannot reliably assess amyloid removal—the primary mechanism of action—though it can provide supportive evidence of treatment response.

The Fundamental Challenge

The absence of a baseline amyloid PET creates a critical gap in monitoring because:

• Amyloid PET is the only validated method to directly measure amyloid plaque removal, which is lecanemab's primary therapeutic mechanism 1
• The Society of Nuclear Medicine and Molecular Imaging (June 2024) states that amyloid PET/CT is appropriate to monitor response in patients receiving approved amyloid-targeting therapy 1
• Without baseline amyloid burden quantification, you cannot determine the magnitude of amyloid reduction achieved or whether therapeutic targets have been met 1

Post-Treatment Amyloid PET Assessment

The most direct approach is to obtain an amyloid PET scan after completing 18 months of lecanemab treatment:

• After 18 months (Week 79) of lecanemab 10 mg/kg biweekly, 67% of patients achieved amyloid levels below 30 Centiloids 2
• A post-treatment scan showing amyloid levels below 24-30 Centiloids indicates substantial amyloid clearance, even without baseline comparison 3
• Values above 30 Centiloids suggest incomplete response, though interpretation is limited without knowing the starting burden 2

Critical limitation: Without baseline values, you cannot calculate the actual reduction achieved (e.g., the 60-85 Centiloid reductions typically seen), only assess the absolute post-treatment level 3

Plasma P-Tau 217 as a Monitoring Tool

Plasma p-tau 217 can provide supportive but not definitive evidence of treatment response:

What P-Tau 217 Can Tell You

• Lecanemab treatment produces significant reductions in plasma p-tau 217 levels compared to placebo 3
• In clinical trials, lecanemab 10 mg/kg biweekly reduced plasma p-tau 181 (a closely related biomarker) by approximately 1.2 pg/mL from baseline at 18 months, versus an increase of 0.08-0.20 pg/mL with placebo 2
• A reduction or stabilization in p-tau 217 suggests treatment is affecting tau pathophysiology downstream of amyloid clearance 3, 2

Critical Limitations of P-Tau 217 for This Purpose

• P-tau 217 reflects tau pathophysiology, not amyloid burden directly—it cannot confirm that amyloid plaques have been removed 1, 3
• During off-treatment periods in clinical trials, plasma biomarkers (including Aβ42/40 ratio and p-tau) returned toward pre-treatment levels more quickly than amyloid PET, indicating they are less stable markers of amyloid status 4
• P-tau 217 changes can be influenced by factors beyond lecanemab's amyloid-clearing effects 3
• There is no established threshold or magnitude of p-tau 217 reduction that correlates with adequate amyloid clearance 3, 2

Practical Monitoring Algorithm Without Baseline PET

Given the limitations, here is the most evidence-based approach:

1. Obtain post-treatment amyloid PET at 18 months to assess absolute amyloid burden 1

   • Target: <30 Centiloids indicates substantial clearance 2
   • 30-50 Centiloids suggests partial response

   • 50 Centiloids indicates inadequate response

2. Measure plasma p-tau 217 (or p-tau 181) at baseline and 18 months 3, 2

   • Look for reduction or stabilization versus expected increase
   • Use as supportive evidence only, not primary endpoint

3. Assess plasma Aβ42/40 ratio at baseline and 18 months 2, 4

   • Lecanemab increases this ratio by approximately 0.007-0.008 from baseline 2
   • Provides additional supportive evidence of amyloid engagement

4. Monitor clinical outcomes using CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL 2, 5

   • Stabilization or slower decline than expected suggests clinical benefit
   • However, clinical measures alone cannot confirm amyloid removal 1

Important Caveats

• MRI monitoring for ARIA remains mandatory regardless of amyloid monitoring strategy, as only MRI can detect these potentially serious complications 1
• The lack of baseline amyloid PET fundamentally limits your ability to quantify treatment response and make informed decisions about continuing, stopping, or modifying therapy 1, 3
• If considering extended or maintenance dosing beyond 18 months, amyloid PET quantification becomes even more critical for decision-making 3, 2

Clinical Bottom Line

The absence of baseline amyloid PET represents a significant gap in monitoring that cannot be fully compensated for by plasma biomarkers alone. The best available approach is to obtain a post-treatment amyloid PET to assess absolute amyloid burden, supplemented by plasma p-tau 217 and Aβ42/40 ratio measurements as supportive evidence of biological response 1, 3, 2. However, this approach cannot determine the magnitude of amyloid reduction achieved or confirm that the patient had adequate baseline amyloid burden to justify treatment in the first place 1.