Highlights
The API ADAD Colombia trial investigated whether crenezumab, an anti-amyloid monoclonal antibody, could delay cognitive decline in a unique cohort of individuals genetically predisposed to early-onset Alzheimer’s disease. Despite a robust 5-to-8-year treatment period, the study found no statistically significant difference between the crenezumab and placebo groups regarding the annualized rate of change in cognitive scores. Furthermore, the treatment did not demonstrate a significant impact on amyloid plaque removal or other key biomarkers, reinforcing the hypothesis that high-affinity fibrillar amyloid clearance may be a prerequisite for clinical efficacy.
Background: The Challenge of Early Intervention in Alzheimer’s
Alzheimer’s disease (AD) remains one of the most significant challenges in modern clinical medicine. While most cases are sporadic and occur later in life, a small percentage of patients suffer from autosomal-dominant Alzheimer’s disease (ADAD), caused by specific genetic mutations. The PSEN1Glu280Ala mutation, often referred to as the ‘Paisa’ mutation, is particularly notable. Found in a large kindred in Antioquia, Colombia, carriers of this mutation are virtually guaranteed to develop cognitive impairment, typically beginning in their 40s, and progressing to dementia by their early 50s.
The predictability of this disease course provides a unique clinical window for secondary prevention trials. Because the onset of symptoms is highly predictable, researchers can intervene years before the first clinical signs appear. Crenezumab, a humanized monoclonal antibody, was designed to target multiple forms of amyloid beta (Aβ), with a specific affinity for neurotoxic oligomers. Unlike other antibodies that target fibrillar plaques and risk inducing amyloid-related imaging abnormalities (ARIA), crenezumab’s IgG4 backbone was engineered to minimize inflammatory responses in the brain, theoretically offering a safer profile for long-term preventative use.
Study Design and Methodology
The API ADAD Colombia Trial Framework
The API ADAD Colombia trial was a Phase 2, randomized, double-blind, placebo-controlled, single-center study. It screened 619 members of the Colombian PSEN1 kindred, eventually enrolling 252 participants. Of these, 169 were mutation carriers who were cognitively unimpaired at baseline (defined by a Clinical Dementia Rating of 0). The primary objective was to evaluate the efficacy and safety of crenezumab in preventing or delaying cognitive decline over a common-close period of 5 to 8 years.
The trial utilized a complex randomization structure to maintain the masking of genetic status. Carriers were randomized 1:1 to crenezumab or placebo, while a group of non-carriers also received placebo to ensure that participants and investigators could not infer a participant’s mutation status based on their treatment assignment. The primary efficacy outcomes were measured using two major tools: the Alzheimer’s Prevention Initiative (API) preclinical ADAD composite test total score and the Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI).
Intervention and Dose Escalation
The trial underwent several protocol amendments to reflect the evolving understanding of amyloid-targeting therapies. Initially, participants received 300 mg of crenezumab subcutaneously every two weeks. This was later increased to 720 mg every two weeks. In the final years of the study, an optional protocol amendment allowed participants to transition to an intravenous dose of 60 mg/kg every four weeks, significantly increasing the total drug exposure in hopes of achieving a measurable clinical effect.
Key Findings: Safety and Efficacy Outcomes
Primary Efficacy Endpoints
The results of the trial, while providing a wealth of data for the scientific community, did not support the efficacy of crenezumab in this population. The annualized rate of change in the API ADAD composite score was -1.10 in the crenezumab group compared to -1.43 in the placebo group. While the crenezumab group numerically declined at a slower rate, the between-group difference of 0.33 (95% CI -0.48 to 1.13) was not statistically significant (p=0.43).
Similarly, the FCSRT-CI, which specifically measures memory function, showed an annualized rate of change of -0.03 in the crenezumab group and -0.04 in the placebo group. The between-group difference of 0.01 (95% CI 0.00 to 0.02) also failed to reach statistical significance (p=0.16). These results indicate that despite years of treatment, crenezumab did not meaningfully alter the trajectory of cognitive decline in these high-risk individuals.
Secondary and Exploratory Biomarkers
The lack of clinical efficacy was mirrored by the biomarker data. Exploratory analyses showed that crenezumab had no significant effect on the removal of existing amyloid plaques, as measured by PET imaging, nor did it significantly impact other downstream biomarkers of neurodegeneration, such as tau protein levels or brain volume loss. This stands in contrast to recent successful trials of other monoclonal antibodies like lecanemab and donanemab, which have shown that robust clearance of fibrillar amyloid plaques is associated with a slowing of clinical progression.
Safety and Tolerability Profile
On a more positive note, the safety data confirmed that crenezumab was generally well-tolerated. Serious adverse events occurred in 27% of the crenezumab group compared to 25% of the placebo group, a difference that was not clinically concerning. Importantly, there were no cases of symptomatic ARIA-E (edema) or ARIA-H (hemorrhage) reported, validating the safety-first design of the IgG4 antibody. However, the lack of safety concerns was overshadowed by the lack of clinical benefit.
Expert Commentary: Analyzing the ‘Amyloid Hypothesis’ in ADAD
The Oligomer vs. Plaque Debate
The failure of the API ADAD trial raises critical questions about the mechanism of action required for Alzheimer’s therapies. Crenezumab was specifically designed to bind to Aβ oligomers—small, soluble aggregates that are thought to be more neurotoxic than the large, insoluble plaques. The theory was that by neutralizing these oligomers, the drug could prevent synaptic dysfunction even without clearing existing plaques. However, the results from this trial, alongside the success of plaque-clearing agents, suggest that once the amyloid cascade has reached a certain threshold, clearing the fibrillar plaque burden may be necessary to realize a clinical benefit.
Methodological Lessons for Future Trials
Despite the negative primary outcome, the API ADAD trial is considered a landmark study in the field of Alzheimer’s prevention. It proved that a large-scale, long-term clinical trial could be successfully conducted within a remote kindred in Colombia. The data generated regarding the natural history of the PSEN1 mutation is invaluable, providing a detailed map of how cognitive scores and biomarkers change years before dementia sets in. This data will be used to refine the design of future prevention trials, including the selection of more sensitive endpoints and the determination of the optimal time for intervention.
Conclusion: The Legacy of the API ADAD Trial
The API ADAD Colombia trial concludes that crenezumab is not an effective treatment for slowing cognitive decline in cognitively unimpaired PSEN1 mutation carriers at the doses tested. While disappointing for the families involved, the study provides a definitive answer regarding this specific therapeutic approach. The focus of the Alzheimer’s research community is now shifting toward even earlier interventions and the use of combination therapies that target both amyloid and tau pathways. The Colombian kindred remains a vital partner in this global effort, and their participation continues to move the field closer to a future where Alzheimer’s disease can be prevented before it ever begins.
Funding and ClinicalTrials.gov
The trial was funded by the US National Institute on Aging (NIA), the Banner Alzheimer’s Institute, Genentech, and F. Hoffmann-La Roche. It is registered with ClinicalTrials.gov under the identifier NCT01998841.
References
Tariot PN, Lopera FS, Ríos-Romenets S, et al. Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at risk for autosomal-dominant Alzheimer’s disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2026 Feb;25(2):147-159. doi: 10.1016/S1474-4422(25)00426-0. PMID: 41579901.
