New TRAC Framework Defines Which Patients Clear Brain Amyloid on Anti-Amyloid Antibody Therapy

Anti-amyloid monoclonal antibodies are now approved and used in clinics, but trials used inconsistent terms and thresholds for patients whose amyloid-PET scans turned negative. Clinicians and researchers need a common vocabulary to guide management and design future studies. An Alzheimer's Association-convened workgroup of academic clinicians and scientists reviewed the literature and proposed one.

The proposed term is treatment-related amyloid clearance (TRAC). It applies to people who (1) had biomarker-confirmed amyloid deposition before treatment, (2) received an amyloid-targeting therapy, and (3) have a follow-up test showing partial or full normalization. For now the group endorses only amyloid-PET for the follow-up test and emphasizes quantitative measures such as Centiloids. Full TRAC means PET has returned to the negative range. Partial TRAC means a significant decrease that remains above the positivity criterion, a category not systematically reported before.

The review of trial data shows full TRAC rates at the longest follow-up of roughly 27-28% for gantenerumab, 31-48% for high-dose aducanumab, 68% for lecanemab in Clarity AD (<30 CL), and 68-76% for donanemab (<24.1 CL). In TRAILBLAZER-ALZ 4, 70% on donanemab reached full TRAC at 12 months versus 22% on aducanumab. Higher doses, longer treatment and lower baseline amyloid predicted full TRAC; in one analysis, those reaching it within 24 weeks started at about 93 CL versus 117 CL. Fluid markers changed less than PET: plasma p-tau217 fell under 40% and did not normalize, which fits the finding that these drugs do not lower tau-PET burden. Gantenerumab changed fluid markers comparably to approved drugs despite a weaker PET effect.

The authors stress that TRAC is a dynamic, biomarker-defined state, not neuropathological proof and not a cure. After donanemab was stopped, amyloid re-accumulated at about 3.4 CL/year, and modeling suggests a median of about 3.9 years to exceed the threshold. A negative PET after treatment should not be read as absence of AD, and biomarker relationships may differ from those in untreated disease.

Autopsy evidence is thin. None of the published treated cases showed complete plaque clearance, and none had full TRAC before death. Cases with partial clearance showed altered plaque morphology, persistent amyloid angiopathy and inflammatory changes, particularly with ARIA. The framework is expected to evolve as blood biomarkers, real-world data and autopsy findings accumulate.