Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.
Madrid L., Moreno-Grau S., Ahmad S., González-Pérez A., de Rojas I., Xia R., Martino Adami PV., García-González P., Kleineidam L., Yang Q., Damotte V., Bis JC., Noguera-Perea F., Bellenguez C., Jian X., Marín-Muñoz J., Grenier-Boley B., Orellana A., Ikram MA., Amouyel P., Satizabal CL., Alzheimer’s Disease Neuroimaging Initiative (ADNI)* None., EADI consortium, CHARGE consortium, GERAD consortium, GR@ACE/DEGESCO consortium None., Real LM., Antúnez-Almagro C., DeStefano A., Cabrera-Socorro A., Sims R., Van Duijn CM., Boerwinkle E., Ramírez A., Fornage M., Lambert J-C., Williams J., Seshadri S., ADAPTED consortium None., Ried JS., Ruiz A., Saez ME.
Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.