Statistical analyses and sample size estimation
The sample size estimate has been detailed previously [All non-MRI analyses were conducted by ANCOVA using mixed models for repeated measures with SAS PROC MIXED. INTERVENTION was fitted as a fixed between-group factor (2 levels: intervention or control group). For non-MRI data, change from baseline was calculated for all outcome variables (ie, 3 mo – 0 mo and 12 mo – 0 mo), and VISIT was fitted as a fixed repeated factor (2 levels: 3 and 12 mo). For MRI data, the 0-mo and 12-mo absolute data was fitted as a 2-level repeated factor. INTERVENTION×VISIT interaction was fitted to the model. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. The LSMEANS statement was used to perform pairwise comparisons between the 2 intervention groups, both overall and at each individual time point. The LSMeans estimates were calculated together with the BASELINE (predose scores) and study site were fitted as covariates. Additional potential covariates included, MCI/SCI status, For the MRI analysis, estimated total intracranial volume, education attainment, and center were added as covariates to the model. The MRI data was evaluated according to the change from an initial baseline scan, thereby overcoming any heterogeneity introduced into the data due to differences in the instruments used at the study sites. Postprocessing of the MRI measures obtained at both sites was conducted at the Biomedical Imaging Center (University of Illinois) to ensure consistency across sites. The effect of group was determined by a univariate ANOVA on the absolute change from 0 to 12 mo (SPSS Version 28.0.1.0). All participants selected for the main per protocol (PP) analyses had completed the entire study and were free of major protocol violations (including medication violations and an overall intervention product compliance of <80%). As a supportive analysis, an intention-to-treat analysis was conducted including all subjects who received at least 1 dose of the study intervention and had postintervention data available. This analysis included CONSORT flowchart diagram. A total of SAS software (STAT 15.1) was used for all statistical analyses