Alzheimer's Imaging Consortium

Abstract

Background: Age, female sex and the APOEe4 allele are among the top risk factors for developing late-onset Alzheimer's disease (LOAD). Precision medicine for AD drug development necessitates targeting specific biological pathways driving AD pathology. We previously identified LOAD-associated transcriptomic signatures specific to both sex and APOE genotype. Here we extend these analyses to examine the association between these signatures and imaging-derived phenotypes (IDPs).

Method: Brain RNA-Seq datasets from ROSMAP (syn8456637) were obtained from the RNA-Seq Harmonization Study on AMP-AD, including 369 frontal cortex samples from APOEe3/e3 and APOEe3/e4 individuals. Differentially expressed genes (DEGs, p-value<0.01) between LOAD and cognitively normal controls were identified for each sex-genotype. IDPs were generated from 1155 individuals in ROSMAP, with 62 overlapping the RNA-Seq Harmonization Study. T1-weighted MRIs were processed using Fastsurfer (v.2.0.4), and cortical thickness (CT) and subcortical volumes (SV) were computed. After multi-site harmonization and covariate adjustment, effect sizes (Cohen's d) for controls vs. AD were computed for each sex-genotype pairing. Correlations between these effect sizes and median regional DEG expression from the Allen Human Brain Atlas were examined.

Result: Controls showed anticipated CT and SV patterns, though male APOEe4s exhibited greater CT in more regions. Higher median expression of up (female APOEe3/e3, male APOEe4) and down (female APOEe3/e3, male APOEe3/e3, male APOEe4) regulated DEGs correlated with less CT in AD patients (r=0.21-0.41, p < 0.046). In APOEe4 carriers, higher median up (male, female) and down (female) DEG expression correlated with greater SV in AD patients (r=0.48-0.57, p < 0.043). Greater median downregulated DEG expression in APOEe3/e3s correlated with smaller SV (r=0.56, p=0.021). Higher median APOE expression was correlated with less CT in AD patients across sex-genotype pairings (r=0.38-0.86, p < 0.002), lower SV (females, all genotypes), and greater SV (male APOEe3/e3). No associations between median DEG expression and CT were observed in female APOEe4 carriers.

Conclusion: Our analyses reveal novel sex and APOE genotype-specific transcriptomic signatures associations with imaging-derived features in LOAD. Our findings transcriptome signature specific CT and SV profiles that may inform therapeutic targets. The present analyses provide support the identification and use of risk-factor specific biomarkers of target engagement for preventative and therapeutic interventions.