Association of Ventricular Size on Executive Function and Attention is Modified by Apolipoprotein E and Moderated by Pulse Pressure in Alzheimer's Disease

AbstractBackgroundGenetic, structural imaging, and vascular risk factors are key determinants of cognitive differences in Alzheimer’s disease (AD). We investigated synergistic associations between three risk factors from each domain on cognition in AD. We focused on (1) whether structural imaging predicts cognitive performance, (2) and is differentially represented by genetic risk and (3) further moderated by vascular risk. Specifically, whether ventricular enlargement predicts EF and attention and whether this is differentially represented by Apolipoprotein E(APOE) and further moderated by pulse pressure (PP).MethodsWe used AD patients (n=321; mean age=71.6(9.6) years; %female=53) from the Sunnybrook Dementia Study (SDS). First, we performed a confirmatory factor analysis to build EF and attention latent factors using five standardized cognitive tests (EF:Wisconsin card sorting test, digit symbol substitution, phonemic fluency, attention:forward and backward digit span). Second, we tested whether ventricular size predicts EF and attention performance at baseline. Third, we tested an APOE effect modification where a different relationship is observed for ventricular size on EF and attention in context of APOE stratification. Fourth, we tested whether PP moderates any effect modification by APOE risk on ventricular size and EF and attention. PP was calculated using systolic minus diastolic blood pressure and divided into low and high groups using the mean PP.ResultsThe best fitting model was observed with a two factor EF and attention model (χ2(df)= 4.059(4),p=0.3981; RMSEA (90% CI)=0.007(0.000‐0.085); CFI=1.000; SRMR= 0.023). Increase in ventricular size predicted lower EF (β=‐10.743, SE=4.538, p=0.018) and attention (β=‐13.342, SE=4.762, p=0.005) performance only in the APOE ɛ4+ risk group. This APOE effect modification was further moderated by PP where only APOE ɛ4+ risk carriers with low PP had poorer EF (β=‐16.553, SE=6.002, p=0.006) and attention (β=‐17.054, SE=6.225, p=0.006) performance with higher ventricular size.ConclusionsEF and attention risk associated with ventricular enlargement was only present in AD patients carrying the APOE ɛ4 allelic risk and further magnified in adults with low PP. Genetic risk stratification in combination with structural imaging and modifiable vascular risk factors may identify AD patients at magnified risk for accelerated decline with potential opportunities for novelinterventions and precision medicine.