API ADAD Colombia
(2026)Objective
To evaluate the efficacy and safety of crenezumab in cognitively unimpaired PSEN1 Glu280Ala mutation carriers at near-certain risk for autosomal-dominant Alzheimer's disease, assessing whether treatment could delay or prevent the onset of cognitive impairment.
Study Summary
• Secondary and exploratory outcomes showed no significant effect on amyloid plaque removal or other clinical or biomarker measures
• Serious adverse events were comparable (27% crenezumab vs 25% placebo) with no fatalities
• Robust fibrillar amyloid removal, not achieved by crenezumab, appears necessary for clinical efficacy based on these and other anti-amyloid trial results
Intervention
Subcutaneous crenezumab 300 mg every 2 weeks (escalated to 720 mg SC every 2 weeks), with optional further escalation to 60 mg/kg IV every 4 weeks; treatment duration 5–8 years
Inclusion Criteria
PSEN1 Glu280Ala kindred membership; age 30–60 years; cognitively unimpaired and medically stable; having a study partner; no history of Alzheimer's disease treatment; body weight 45–120 kg
Study Design
Arms: Crenezumab–mutation carrier (n=85) vs Placebo–mutation carrier (n=84); Placebo–non-carrier (n=83) as genetic kindred control
Patients per Arm: Crenezumab: 85; Placebo-carrier: 84; Placebo-non-carrier: 83
Outcome
• FCSRT-CI: annualized rate of change −0.03 (crenezumab) vs −0.04 (placebo); difference 0.01 (95% CI 0.00 to 0.02), p=0.16
• Serious adverse events: 23/84 (27%) crenezumab vs 21/84 (25%) placebo; no fatalities
• No significant effect on amyloid removal or secondary/exploratory biomarker endpoints
Bottom Line
Crenezumab administered for 5–8 years did not prevent or delay cognitive decline in preclinical autosomal-dominant Alzheimer's disease; robust fibrillar amyloid removal — not achieved by crenezumab — appears necessary for clinical efficacy, and future prevention trials should prioritize agents with demonstrated potent amyloid-clearing capacity.
Major Points
- Neither co-primary endpoint reached statistical significance: API ADAD composite test showed a between-group difference of 0.33 (95% CI −0.48 to 1.13, p=0.43) and FCSRT-CI showed a difference of 0.01 (95% CI 0.00 to 0.02, p=0.16)
- Secondary and exploratory outcomes showed no significant effect on amyloid plaque removal or other clinical or biomarker endpoints
- Crenezumab was generally well tolerated; serious adverse events occurred in 27% (23/84) of the crenezumab group vs 25% (21/84) of the placebo-carrier group, with no fatalities
- The trial enrolled participants up to approximately 16 years before expected symptom onset; with treatment durations of 5–8 years, this represents one of the longest anti-amyloid prevention exposures ever studied
- Amyloid PET positivity was not required for enrollment, meaning some participants may have been amyloid-negative at baseline, potentially diluting any detectable treatment effect
- The dose was escalated progressively during the trial (300 mg SC → 720 mg SC → optional 60 mg/kg IV), suggesting early participants received subtherapeutic exposure
- Combined with other anti-amyloid β trial results, these findings indicate that robust fibrillar amyloid plaque clearance is necessary for clinical benefit — an endpoint crenezumab did not achieve
- Longitudinal biomarker and cognitive data from this trial will inform trajectories of preclinical ADAD and the design of future secondary and primary prevention trials
Study Design
- Study Type
- Phase 2 randomised double-blind placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; investigators and participants masked to treatment allocation; study drug preparers and the Independent Data Monitoring Committee were unmasked
- Sample Size
- 252
- Follow-up
- 5–8 years (common-close design); final data collection March 22, 2022
- Centers
- 1
- Countries
- Colombia
Primary Outcome
Definition: Dual co-primary outcomes: (1) Annualized rate of change in API ADAD composite test total score; (2) Annualized rate of change in FCSRT-CI (Free and Cued Selective Reminding Test–Cueing Index); both assessed via random coefficient regression in randomised participants who received at least one dose
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| API ADAD composite: −1.43 (SE 0.29); FCSRT-CI: −0.04 (SE 0.00) | API ADAD composite: −1.10 (SE 0.29); FCSRT-CI: −0.03 (SE 0.00) | - (API ADAD composite: −0.48 to 1.13; FCSRT-CI: 0.00 to 0.02) | API ADAD composite: p=0.43; FCSRT-CI: p=0.16 |
Limitations & Criticisms
- Crenezumab likely did not achieve sufficient fibrillar amyloid plaque removal to produce clinical benefit; insufficient target engagement at the doses used may fully explain the null result
- Amyloid PET positivity was not required for enrollment, meaning a proportion of participants may have been amyloid-negative at baseline and therefore not candidates for anti-amyloid benefit
- Progressive dose escalation during the trial (300 mg SC → 720 mg SC → optional 60 mg/kg IV) means early enrollees received subtherapeutic exposure for extended periods
- The common-close design produced heterogeneous treatment durations (5–8 years) across participants, complicating interpretation of time-dependent effects
- Findings apply only to the PSEN1 Glu280Ala mutation in a single Colombian kindred, limiting generalizability to other ADAD mutations or sporadic Alzheimer's disease
- Success of blinding procedures was not formally assessed
Citation
Tariot PN, Lopera FS, Ríos-Romenets S, Sink KM, et al. Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1 Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia. Lancet Neurol. 2026;25(2):147-159.