Heterogeneity in Preclinical Alzheimer's Disease Trial Cohort Identified by Image-based Data-Driven Disease Progression Modelling

ImportanceUndetected biological heterogeneity adversely impacts trials in Alzheimers disease because rate of cognitive decline -- and perhaps response to treatment -- differs in subgroups. Recent results show that data-driven approaches can unravel the heterogeneity of Alzheimers disease progression. The resulting stratification is yet to be leveraged in clinical trials. ObjectiveInvestigate whether image-based data-driven disease progression modelling could identify baseline biological heterogeneity in a clinical trial, and whether these subgroups have prognostic or predictive value. DesignScreening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected between April 2014 and December 2017, and longitudinal data from the Alzheimers Disease Neuroimaging Initiative (ADNI) observational study downloaded in February 2022 were used. SettingThe A4 Study is an interventional trial involving 67 sites in the US, Canada, Australia, and Japan. ADNI is a multi-center observational study in North America. ParticipantsCognitively unimpaired amyloid-positive participants with a 3-Tesla T1-weighted MRI scan. Amyloid positivity was determined using florbetapir PET imaging (in A4) and CSF A{beta}(1-42) (in ADNI). Main Outcomes and MeasuresRegional volumes estimated from MRI scans were used as input to the Subtype and Stage Inference (SuStaIn) algorithm. Outcomes included cognitive test scores and SUVr values from florbetapir and flortaucipir PET. ResultsWe included 1,240 A{beta}+ participants (and 407 A{beta}- controls) from the A4 Study, and 731 A4-eligible ADNI participants. SuStaIn identified three neurodegeneration subtypes -- Typical, Cortical, Subcortical -- comprising 523 (42%) individuals. The remainder are designated subtype zero (insufficient atrophy). Baseline PACC scores (A4 primary outcome) were significantly worse in the Cortical subtype (median = -1.27, IQR=[-3.34,0.83]) relative to both subtype zero (median=-0.013, IQR=[-1.85,1.67], P<.0001) and the Subcortical subtype (median=0.03, IQR=[-1.78,1.61], P=.0006). In ADNI, over a four-year period (comparable to A4), greater cognitive decline in the mPACC was observed in both the Typical (-0.23/yr; 95% CI, [-0.41,-0.05]; P=.01) and Cortical (-0.24/yr; [-0.42,-0.06]; P=.009) subtypes, as well as the CDR-SB (Typical: +0.09/yr, [0.06,0.12], P<.0001; and Cortical: +0.07/yr, [0.04,0.10], P<.0001). Conclusions and RelevanceIn a large secondary prevention trial, our image-based model detected neurodegenerative heterogeneity predictive of cognitive heterogeneity. We argue that such a model is a valuable tool to be considered in future trial design to control for previously undetected variance. Key PointsO_ST_ABSQuestionC_ST_ABSCan MRI-based computational subtypes of preclinical neurodegeneration predict cognitive outcomes? FindingsIn this cross-sectional analysis of magnetic resonance imaging (MRI) data at screening (pre-randomization) in the preclinical Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study, we detected considerable neurodegenerative heterogeneity using data-driven disease progression modelling. The MRI-based computational subtypes identified by Subtype and Stage Inference (SuStaIn) differed in baseline cognitive test scores (A4) and in longitudinal cognitive decline (ADNI), with sufficient heterogeneity to potentially obscure treatment effect in A4 trial outcomes. MeaningData-driven disease progression modelling of screening MRI scans can predict heterogeneity in cognitive performance/decline and potentially reduce heterogeneity in future clinical trials.