Alzheimer's Imaging Consortium | JoVE Visualize

Area of Science:

Neuroscience
Clinical Trials
Biostatistics

Background:

Amyloid removal is a surrogate outcome for Alzheimer's disease (AD) drug trials.
Drug approvals for AD have utilized the Accelerated Approval Program based on amyloid removal.
Access to individual-level data from anti-amyloid trials has been limited, hindering surrogate outcome validation.

Purpose of the Study:

To demonstrate the utility of epidemiologic and econometric methods for validating amyloid as a surrogate outcome in AD drug trials.
To analyze the impact of amyloid removal on cognitive decline using individual-level data from the A4 trial of solanezumab.
To assess the causal effect of amyloid reduction on cognitive changes and the extent to which amyloid mediates drug effects.

Main Methods:

Utilized individual-level data from 815 participants in the A4 trial (Alzheimer's Clinical Trial Consortium A4/LEARN).
Estimated cognitive change via Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score trajectory over 4.5 years.
Employed instrumental-variable (IV) methods and causal mediation analysis to evaluate amyloid reduction's causal effect on cognition, adjusting for relevant covariates.

Main Results:

Solanezumab showed minimal amyloid reduction (-0.05 SUVr) and cognitive change (0.002 CDR-SB points/month).
No significant non-linear effects of amyloid on cognition were observed.
IV analysis indicated an imprecise effect of amyloid reduction on cognitive change (95% CI: -0.096, 0.014).
Mediation analysis suggested amyloid change mediated 23% of solanezumab's cognitive effect, with wide confidence intervals (-125%, 253%).

Conclusions:

Epidemiologic and econometric methods applied to individual-level data can enhance understanding of amyloid as a surrogate outcome for cognition in Alzheimer's disease.
Results from the A4 trial were imprecise due to solanezumab's limited amyloid-clearing efficacy.
Replicating these analyses with data from more effective anti-amyloid therapies is crucial for refining treatment strategies and informing future surrogate outcome use in drug approvals.