In a landmark study published in JAMA (August 2023), the phase 3 TRAILBLAZER-ALZ 2 clinical trial demonstrated that donanemab, an anti-amyloid monoclonal antibody, significantly slowed cognitive and functional decline in individuals with early symptomatic Alzheimer's disease (AD). This rigorous, multinational, double-blind, placebo-controlled trial provides some of the strongest evidence to date for disease modification in Alzheimer's, particularly among patients with confirmed amyloid pathology and low to medium tau burden.
Study Design and Population
TRAILBLAZER-ALZ 2 enrolled 1,736 participants aged 60 to 85 with early symptomatic AD-defined as mild cognitive impairment (MCI) or mild dementia-alongside positive amyloid PET scans and either low/medium or high tau PET pathology. Conducted at 277 centers in 8 countries, the trial randomly assigned participants 1:1 to receive either donanemab (700 mg IV for 3 doses, then 1400 mg every 4 weeks) or placebo, for a total treatment period of 72 weeks.
Treatment was adjusted if amyloid clearance benchmarks were met based on PET Centiloid thresholds, allowing for a personalized de-escalation strategy. This adaptive protocol is unique and reflects a broader goal of optimizing safety while preserving efficacy.
Key Efficacy and Safety Results
Table 1. Clinical Outcomes and Adverse Events at 76 Weeks
| Outcome | Donanemab | Placebo | Treatment Effect |
|---|---|---|---|
| Primary Outcome | |||
| iADRS change (low/medium tau) | −6.02 | −9.27 | +3.25 points (35.1% slower decline, P < .001) |
| iADRS change (combined population) | −10.19 | −13.11 | +2.92 points (22.3% slower decline, P < .001) |
| Secondary Outcomes (low/medium tau) | |||
| CDR-SB change | +1.20 | +1.88 | −0.67 points (36.0% slower decline, P < .001) |
| ADAS-Cog13 change | −2.23 | −3.75 | +1.52 points (32.4% slower decline) |
| ADCS-iADL change | −3.15 | −4.98 | +1.83 points (39.9% slower decline) |
| Risk of clinical progression (CDR-Global) | 18.0% | 28.0% | 38.6% risk reduction, HR: 0.61 (P < .001) |
| % Stable at 1 year (no CDR-SB decline) | 47% | 29% | +18% absolute benefit (P < .001) |
| Biomarker Results (Combined Population) | |||
| Amyloid PET clearance (at 76 weeks) | 76.4% | 0.3% | Substantial amyloid reduction |
| Plasma P-tau217 change (log10) | −0.22 | - | Significant reduction, P < .001 |
| Tau PET frontal SUVR | No significant difference | - | - |
| Adverse Events (Combined Population) | |||
| Any ARIA-E (edema/effusion) | 24.0% (52 symptomatic) | 2.1% (0 symptomatic) | Most events mild/moderate and resolved |
| ARIA-H (microhemorrhage/hemosiderin deposits) | 31.4% | 13.6% | Increased MRI-detected events |
| Infusion-related reactions | 8.7% | 0.5% | |
| Serious adverse events | 17.4% | 15.8% | |
| Deaths (treatment-related) | 3 | 1 | All in donanemab group involved ARIA |
Interpretation and Clinical Implications
Donanemab provides a clinically meaningful benefit for individuals with early Alzheimer's disease, especially those with low or medium tau pathology. This benefit is evident across cognitive, functional, and global measures, with an average delay in disease progression ranging from 4 to 7.5 months depending on the outcome metric.
Crucially, the trial underscores the need for biomarker-based patient selection. Patients with high tau pathology demonstrated attenuated treatment response, likely reflecting more advanced neurodegeneration.
While donanemab is associated with an increased risk of amyloid-related imaging abnormalities (ARIA), most cases were manageable with monitoring and did not lead to permanent harm. However, APOE ε4 carriers remain a higher-risk subgroup.
Clinical Implications
Donanemab is among the first anti-amyloid agents to demonstrate clinically meaningful slowing of disease progression in early symptomatic Alzheimer's disease, particularly in individuals with lower tau burden. While the treatment poses real safety considerations-especially related to ARIA-it offers a potentially disease-modifying option for a carefully selected patient population.
Notably, donanemab's biomarker-guided protocol, including PET-confirmed amyloid and tau status, introduces a precision medicine approach to AD treatment-moving the field beyond symptomatic care and toward pathology-targeted intervention.
Conclusion
The TRAILBLAZER-ALZ 2 trial provides compelling evidence that donanemab can significantly slow cognitive and functional decline in patients with early Alzheimer's disease. As AD treatment enters a new era of biologics and biomarker-driven care, donanemab represents a major step forward-but requires careful patient selection and ongoing monitoring to balance its therapeutic benefits against its risks.
