Donanemab, an amyloid-targeting monoclonal antibody, significantly slows clinical decline in patients with early symptomatic Alzheimer’s disease (AD).¹ However, the long-term durability of treatment effects between early completers and participants requiring continued treatment beyond the core study period remains unclear.¹ At the AAN Annual Meeting 2026, Dr. Curtis Schreiber from the Missouri Memory Center, United States, presented findings from the TRAILBLAZER-ALZ 2 long-term extension (LTE) study, demonstrating sustained clinical and biomarker benefits of donanemab over 3 years after treatment discontinuation.¹

The TRAILBLAZER-ALZ 2 study consisted of a 76-week randomized, placebo-controlled core study followed by a 78-week double-blind LTE period evaluating intravenous donanemab.¹ Participants were randomized 1:1 to receive either placebo or intravenous donanemab (700mg every 4 weeks [Q4W] for the first 3 doses followed by 1,400mg Q4W thereafter).¹ The study uniquely applied amyloid positron emission tomography (PET)-guided stopping criteria.¹ Participants achieving predefined amyloid plaque clearance thresholds (<11 centiloids on a single PET scan or <25 centiloids on 2 consecutive PET scans) were transitioned from donanemab to placebo (DONA-PBO cohort).¹ Participants who did not meet stopping criteria by week 76 continued donanemab treatment into the LTE period (DONA-DONA cohort).¹

The analysis focused on “early-start” participants who initiated donanemab during the core study period and entered the LTE (DONA-DONA and DONA-PBO cohorts).¹ Approximately 71% of these participants entered the LTE after completing their treatment course.¹ In contrast, participants who required ongoing donanemab during the LTE (DONA-DONA) generally presented with a higher baseline disease burden, characterized by a higher baseline amyloid plaque load (~122 vs. 94.8 centiloids) and a higher apolipoprotein E ε4 (APOE ε4) prevalence (80.3% vs. 63.4%).¹ Long-term clinical outcomes were compared against an external historical Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to evaluate 3-year treatment durability.¹

Clinical efficacy analyses demonstrated a sustained separation in Clinical Dementia Rating Sum of Boxes (CDR-SB) trajectories between the early-start donanemab cohort (who completed treatment by week 52) and the external ADNI cohort over 3 years, confirming that clinical benefits persist long after treatment discontinuation.¹ Notably, no significant differences in clinical outcomes were observed between the DONA-PBO and DONA-DONA groups, suggesting that extended treatment allowed the higher-burden cohort to achieve comparable clinical stabilization.¹ Biomarker analyses further supported this durability.¹ Among participants meeting treatment completion criteria by week 52, mean amyloid plaque levels remained below 24.1 centiloids throughout the LTE period despite approximately 2 years off therapy.¹ At 3 years, the mean centiloid value remained at 11, while modeled amyloid plaque reaccumulation over time was consistent with the natural history of AD.¹ Notably, 56.8% of participants continuing donanemab into the LTE ultimately achieved amyloid plaque clearance by the end of the LTE period, demonstrating durable amyloid reduction even among participants requiring prolonged treatment.¹

Safety findings demonstrated that participants in the DONA-DONA cohort experienced higher frequencies of amyloid-related imaging abnormalities (ARIA) during the core placebo-controlled period compared to those who transitioned to placebo early.¹ This included higher rates of ARIA-edema (24.2% vs. 19.1%) and ARIA-hemosiderin (24.2% vs. 18.6%).¹ During the core period, treatment interruptions were more frequent and prolonged in the continuous-treatment group (43% and 14.4 weeks, respectively) than in the early-transition group (31% and 9.3 weeks, respectively).¹ Infusion-related reaction (IRR) incidence during the placebo-controlled period was also numerically higher among participants continuing donanemab (7.6% vs. 4.8%).¹ Reassuringly, no new safety signals were identified during long-term follow-up.¹

In summary, analyses from the TRAILBLAZER-ALZ 2 LTE study demonstrated durable clinical and biomarker effects of donanemab in patients with early symptomatic AD.¹ Most participants achieved amyloid plaque clearance, with sustained clinical benefits following treatment discontinuation and reduced cumulative donanemab exposure over 3 years.¹ These findings support the clinical strategy of early, robust amyloid clearance and validate the safety and utility of a flexible, PET-guided dosing paradigm.¹