Alzheimer’s disease (AD) remains a significant global health challenge.¹ Approvals of anti-amyloid antibodies by the United States Food and Drug Administration (FDA) have reinforced confidence in the therapeutic potential of anti-amyloid therapies, which represent an advanced class of disease-modifying approaches.² However, the relationship between amyloid clearance and meaningful clinical outcomes has been inconsistent across studies.² In this context, a new secondary analysis of the phase 3 TRAILBLAZER-ALZ 2 trial provides additional evidence, showing that lower posttreatment amyloid levels are associated with slower clinical decline and favorable changes in AD-related biomarkers, thereby strengthening the correlation between amyloid clearance and meaningful patient outcomes.³

With over 50 million people affected globally and prevalence rising sharply in ageing populations, dementia—and particularly AD—continues to drive a significant burden of disability-adjusted life-years (DALYs) in individuals aged 75 and older.¹ Amyloid-β accumulation remains a fundamental driver of AD pathophysiology.³ Donanemab, an amyloid-targeting monoclonal antibody, previously demonstrated substantial amyloid reduction and slowed clinical decline in the TRAILBLAZER-ALZ 2 trial, with reductions of 87 Centiloids over 76 weeks and relative slowing of clinical progression by 22.3% on the integrated Alzheimer’s Disease Rating Scale (iADRS) and 28.9% on the Clinical Dementia Rating-Sum of Boxes (CDR-SB).³ Despite these promising results, correlations between amyloid reductions and clinical or biomarker outcomes have been inconsistent across analyses from earlier trials.³ The captioned post hoc exploratory analysis was therefore conducted to evaluate the association between posttreatment amyloid burden and subsequent changes in both clinical measures and plasma biomarkers within the TRAILBLAZER-ALZ 2 population.³

The analysis included 1,582 participants from TRAILBLAZER-ALZ 2, which was a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of donanemab in early symptomatic AD.³ Of these, 766 received donanemab and 816 received a placebo.³ The participants were 60-85 years of age and had PET-confirmed amyloid and tau pathology.³ Amyloid burden was assessed using ¹⁸F-florbetapir or ¹⁸F-florbetaben positron emission tomography (PET) imaging at baseline and at 24, 52, and 76 weeks.³ Clinical progression over 76 weeks was measured using the iADRS and CDR-SB, while plasma biomarkers—including p-tau217, p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)—were evaluated over the same interval.³ The post hoc analysis included all participants with baseline and at least one posttreatment assessment.³ To enable a detailed examination of outcomes across the full spectrum of amyloid reduction, participants were further classified into 10 groups (deciles) based on their lowest observed posttreatment amyloid value, with the median level of each decile used to correlate with estimated mean changes in clinical assessments in correlation analyses.³

The mean participant age was 72.9 years, and 56.9% were female.³ Nearly all participants in the lowest three deciles—representing the greatest amyloid reduction—received donanemab, and 99.6% of those in these deciles achieved amyloid clearance below 24.1 Centiloids by week 76.³ Across the full study population, lower posttreatment amyloid levels were strongly associated with slower clinical progression.³ Posttreatment amyloid PET values were correlated with clinical outcomes, with an R² of 0.73 for iADRS change (95% CI: 0.37-0.97) and 0.87 for CDR-SB change (95% CI: 0.70-0.97), indicating that participants with the lowest posttreatment amyloid burdens experienced the least cognitive and functional decline.³

Similarly, lower posttreatment amyloid levels were also strongly associated with favorable changes in several plasma biomarkers of AD pathology.³ Greater amyloid reduction correlated with larger decreases in p-tau217 (R²=0.86; 95% CI: 0.73-0.97), p-tau181 (R²=0.88; 95% CI: 0.77-0.97), and GFAP (R²=0.87; 95% CI: 0.76-0.97), indicating close alignment between amyloid clearance and downstream biological effects.³ In contrast, neurofilament light chain (NfL) showed no meaningful association with posttreatment amyloid burden (R²=0.03; 95% CI: 0.00-0.54).³

In summary, this secondary analysis of TRAILBLAZER-ALZ 2 provides evidence that lower posttreatment amyloid burden is associated with slower clinical decline and favorable biomarker shifts in early symptomatic AD, reinforcing the central role of amyloid clearance in anti-amyloid therapies.³ These findings support the concept that posttreatment amyloid burden may serve as a potential surrogate biomarker for clinical outcomes and suggest that achieving very low amyloid levels may yield great clinical benefit. ³