In recent years, the development of anti-amyloid antibody therapies has marked progress in Alzheimer's disease treatment. These laboratory-produced proteins are designed to target amyloid plaques in the brain, which are characteristic of Alzheimer's, and aim to slow disease progression by stimulating the immune system.
Biomarkers from PET scans have played a crucial role in the approval of drugs such as lecanumab (Leqembi) and donanemab (Kisulna) by the U.S. Food and Drug Administration (FDA). While these treatments have shown effectiveness in reducing amyloid plaques, there remains a need for better methods to monitor their efficacy and safety.
To address this gap, the Alzheimer's Association brought together a group of scientists and clinicians with expertise in clinical trials and biomarker research related to Alzheimer's. The workgroup proposed a new framework for assessing patient responses to anti-amyloid therapies. Their recommendations were published on November 26 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
"This framework identifies an individual's response to anti-amyloid treatment and will help guide clinical management and decisions to switch treatment, or describe their current amyloid load," said Maria C. Carrillo, PhD, chief science officer and medical affairs lead at the Alzheimer's Association. "Additionally, these measures could be required for inclusion in future trials."
The workgroup was led by Renaud La Joie, PhD, from UCSF. They introduced "Treatment-Related Amyloid Clearance" (TRAC), a standard that uses biomarker evidence—specifically amyloid-PET imaging—to quantify changes in amyloid deposits after therapy. TRAC is intended for patients with confirmed cerebral Aβ deposition who undergo Aβ-targeting treatments.
The TRAC framework provides quantitative measurements based on plaque clearance rather than relying solely on clinical symptoms. It outlines two levels of clearance for amyloid deposits and is designed to adapt over time as new data emerge from ongoing research and real-world use.
"We still have a lot to learn about what these drugs do and how they work," said Renaud La Joie, PhD. "Even though they are being used and prescribed in the real world, there's actually a little bit of a gray area about how to handle them long-term. For example, donanemab treatment may be stopped when a patient reaches full TRAC, similar to the design of the phase 3 clinical trial."
A review conducted by the group found that higher doses and longer durations of anti-Aβ therapy were linked with greater rates of full TRAC within clinical trials. Trials where more participants achieved full TRAC tended also to show more significant slowing of cognitive decline compared with those with lower rates.
"What we tried to do in our workgroup was to create a global framework to help develop best practices in the continued treatment of patients receiving these therapies," said La Joie. "Since plaque clearance correlates highly with symptom improvement, it provides a standard for clinicians to follow in future trials and treatment."
Despite this correlation at group levels within studies, whether changes detected through amyloid-PET scans translate into benefits for individual patients remains uncertain—a key question behind further development of TRAC.
"One thing that we need to emphasize is that TRAC is not about demonstrating a cure. TRAC represents a measure of the disease that is no longer detectable," said La Joie. "While disease is still there, it's a modified version of the disease and there will be continued cognitive decline, but at a slower pace than if they had not been treated. We think TRAC provides clinicians a way to help patients and caregivers better understand the changes in the disease state."
The authors recommend that future research should focus on using biomarkers alongside assessments of clinical outcomes to determine optimal treatment approaches following achievement of TRAC status. This could clarify whether reaching certain biomarker thresholds should prompt changes such as ending therapy or shifting to maintenance dosing strategies. Additionally, plasma-based biomarkers may become important tools since current fluid tests or imaging cannot fully capture all aspects of Alzheimer’s progression.
