Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis

Abstract

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.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“… 287 A large overlap of genes was reported between ε3 and ε4 carriers in an omics study including ADNI data. 288 Functions of these genes were consistent with “typical” AD processes and included mitochondrial physiology, Aβ physiology, vesicle mediated transport, and the immune response. APOE ε2 carriers had a distinct set of genes with novel functions including chromatin remodeling and regulation.…”

“…However, the order estimated for ε2 carriers differed substantially with CSF neurogranin and MMSE predicted as early biomarkers with low confidence, and CSF p‐tau181 preceding CSF Aβ42 abnormality 287 . A large overlap of genes was reported between ε3 and ε4 carriers in an omics study including ADNI data 288 . Functions of these genes were consistent with “typical” AD processes and included mitochondrial physiology, Aβ physiology, vesicle mediated transport, and the immune response.…”

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer’s Disease Model

“…Diving further into the effect of APOE isoforms on this homeostatic microglia cluster, we examined the DEGs in hE4-E4KI microglial cluster 1 versus hE3-E3KI microglial cluster 1. This comparison showed that the hE4-E4KI microglia cluster 1 expressed increased levels of pro-inflammatory and AD-associated genes like Cdk8 (a promoter of NF-κB signaling and chemokine expression) 55,56 , Cmss1 (previously found to be upregulated in APOE4 male mice) 57 , Marcks (associated with cell motility and phagocytosis and highly expressed by senile amyloid plaque-associated microglia) 58,59 , and Tmem176b (expressed highly by amyloid plaque-adjacent microglia and associated with lysosomal degradation) 60 (Figure S7A). Though we cannot determine whether these effects are attributed to microglial or neuronal APOE4, it is clear that APOE4 induces transcriptomic changes toward pro-inflammatory signatures even in homeostatic microglia compared to APOE3.…”

Integrated Genomic, Transcriptomic and Proteomic Analysis for Identifying Markers of Alzheimer’s Disease

“…According to the ROSMAP snRNAseq data and the scREAD database, GPC2 is downregulated in OPCs from AD patients when compared with control subjects. In a previous report, we identified these cells as key drivers in AD pathogenesis [ 39 ]. In fact, myelin disturbance as an etiological agent for AD is now increasingly being studied, and a recent report confirms its key role in a murine model of AD [ 40 ].…”