The recent viewpoint published in The Lancet Regional Health – Europe examines how amyloid positron emission tomography (PET) is transitioning from a primarily diagnostic tool to a key component in managing anti-amyloid therapies for Alzheimer’s disease. Authored by Massimo Filippi, Giordano Cecchetti, Alma Ghirelli, Edoardo G. Spinelli, Giulia Rugarli, Stefano Pisano, Ana Maria Samanes Gajate, Arturo Chiti, and Federica Agosta from the IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University in Milan, Italy, the piece titled “From Target Engagement to Treatment Governance: The Evolving Role of Amyloid PET in Anti-Amyloid Therapy” highlights practical considerations for treatment pathways in real-world clinical settings.
Anti-amyloid monoclonal antibodies such as lecanemab and donanemab represent a shift in Alzheimer’s care. These therapies target amyloid-beta plaques, a hallmark pathology of the disease. While clinical trials demonstrated group-level reductions in amyloid burden, translating these findings into individualized treatment decisions requires robust monitoring strategies. The viewpoint emphasizes that amyloid PET offers quantitative insights into fibrillar amyloid levels that fluid biomarkers alone may not fully capture during ongoing therapy.
Background on Alzheimer’s Disease and Anti-Amyloid Therapies
Alzheimer’s disease involves the accumulation of amyloid-beta plaques and tau tangles in the brain, leading to progressive cognitive decline. For decades, diagnosis relied heavily on clinical symptoms supplemented by cerebrospinal fluid analysis or imaging for confirmation. The approval of disease-modifying therapies has introduced new demands on healthcare systems, including patient selection, monitoring for side effects like amyloid-related imaging abnormalities (ARIA), and decisions about treatment duration.
Lecanemab received approval based on evidence of amyloid reduction and modest clinical benefits in early-stage patients. Donanemab similarly showed plaque clearance in trials, with protocols sometimes incorporating treat-to-clear approaches where therapy stops upon reaching low amyloid thresholds measured in centiloids. These developments have prompted memory clinics to reconsider how biomarkers guide not just initial eligibility but also longitudinal management.
The Shift to Treatment Governance
With therapies now entering routine care, clinicians face questions about how long to continue treatment, when to switch agents, or when to discontinue based on individual responses. The authors argue that amyloid PET can provide a baseline quantitative reference of amyloid burden and allow follow-up scans to assess whether meaningful target engagement has occurred. This approach aligns with emerging frameworks like Treatment-Related Amyloid Clearance (TRAC), which categorizes patients according to biomarker evidence of plaque reduction following therapy.
Unlike plasma or CSF measures that confirm presence of pathology, quantitative PET delivers regional and global estimates of fibrillar amyloid suitable for paired comparisons over time. In practice, this information helps distinguish patterns of response, from substantial clearance to minimal change, informing governance decisions alongside clinical outcomes and safety data.
Insights from Real-World Implementation at San Raffaele
The viewpoint draws on experience from the Center for Alzheimer’s and Related Diseases at IRCCS San Raffaele Scientific Institute. In their structured program, amyloid PET is integrated at baseline and at six-month follow-up for patients receiving anti-amyloid monoclonal antibodies. Of 58 treated patients, 27 had reached the follow-up timepoint with completed PET scans at the time of reporting.
In the lecanemab cohort, several patients were switched to donanemab after follow-up imaging revealed insufficient amyloid reduction. Those who continued on lecanemab exhibited lower residual global amyloid burden and greater reduction compared with those switched. For donanemab, discontinuation decisions incorporated treat-to-clear criteria based on low centiloid values. These observations illustrate how PET findings, interpreted within the full clinical context, support practical adjustments to treatment courses.
Unique Contributions of Amyloid PET
Amyloid PET stands out for its ability to visualize and quantify plaque burden in vivo. Baseline scans establish a reference point for expected changes under therapy. Follow-up scans can reveal whether amyloid levels have declined meaningfully, supporting decisions on continuation or modification. The modality also aids risk stratification for ARIA, a known side effect involving brain swelling or microhemorrhages that requires MRI monitoring.
This quantitative capability complements fluid biomarkers, which excel at confirming biological diagnosis but offer less direct visualization of residual fibrillar deposits for longitudinal tracking. When healthcare resources are limited, selective use of PET may help optimize treatment exposure without unnecessary prolongation or premature cessation.
Limitations and Practical Challenges
The authors stress that amyloid reduction on PET does not equate to proven individual-level clinical benefit. Broader debates continue regarding the net value of these therapies in diverse populations and healthcare settings. Safety considerations, including ARIA risk, infusion burden, and comorbidity management, must factor into any governance framework. Additionally, expanded PET use faces hurdles such as scanner availability, tracer access, reimbursement variability across Europe, radiation exposure, and overall system capacity.
Implementation requires multidisciplinary coordination among neurologists, nuclear medicine specialists, and radiologists. Reimbursement policies and infrastructure developed primarily for diagnostic purposes now need adaptation for treatment-oriented applications.
Implications for Research and Academic Communities
This evolving role of amyloid PET opens avenues for academic inquiry. Researchers in neuroimaging, neurology, and health services can explore optimal scanning intervals, integration with other biomarkers, and cost-effectiveness analyses in different healthcare models. Training programs for clinicians and technologists may need updating to incorporate quantitative PET interpretation in therapeutic contexts.
Institutions with strong memory clinics and imaging facilities are well positioned to contribute real-world evidence. Collaborative studies across European centers could standardize protocols and refine the TRAC framework for broader adoption. Such work aligns with growing emphasis on precision approaches in neurodegenerative disease management.
Future Outlook and Actionable Considerations
As more patients access anti-amyloid therapies, structured pathways incorporating selective longitudinal PET may become standard in high-volume centers. Ongoing research will clarify thresholds for meaningful change and how these integrate with cognitive assessments and safety monitoring. Policymakers and payers will play key roles in determining feasible implementation scales.
For clinicians and researchers, the viewpoint underscores the value of viewing amyloid PET as one layer within a comprehensive governance strategy rather than a standalone solution. Continued dialogue between academic centers, regulatory bodies, and patient advocacy groups will shape balanced, evidence-informed practices.
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