Madrid, LauraMoreno-Grau, SoniaAhmad, ShahzadGonzález-Pérez, Antoniode Rojas, ItziarXia, RuiMartino Adami, Pamela VGarcía-González, PabloKleineidam, LucaYang, QiongDamotte, VincentBis, Joshua CNoguera-Perea, FuensantaBellenguez, CélineJian, XueqiuMarín-Muñoz, JuanGrenier-Boley, BenjaminOrellana, AdelaIkram, M ArfanAmouyel, PhilippeSatizabal, Claudia LAlzheimer’s Disease Neuroimaging Initiative (ADNI)*EADI consortium, CHARGE consortium, GERAD consortium, GR@ACE/DEGESCO consortiumReal, Luis MiguelAntúnez-Almagro, CarmenDeStefano, AnitaCabrera-Socorro, AlfredoSims, RebeccaVan Duijn, Cornelia MBoerwinkle, EricRamírez, AlfredoFornage, MyriamLambert, Jean-CharlesWilliams, JulieSeshadri, SudhaADAPTED consortiumRied, Janina SRuiz, AgustínSaez, Maria Eugenia2025-01-072025-01-072021-04-12https://hdl.handle.net/10668/25121Alzheimer'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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/APOEAlzheimer’s diseasebiomarkersintegrative analysisresearch article33846280open access10.18632/aging.2029501945-4589PMC8064208https://doi.org/10.18632/aging.202950https://pmc.ncbi.nlm.nih.gov/articles/PMC8064208/pdf