Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease

Rebecca Panitch,Thor D Stein,Weiming Xia,Junming Hu,Lindsay A Farrer,Gyungah R Jun,David A Bennett

doi:10.1186/s13195-022-00975-z

Rebecca Panitch, Thor D Stein + Show 5 more

Open Access

https://doi.org/10.1186/s13195-022-00975-z

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Abstract

BackgroundWhile Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for the diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood-brain barrier (BBB) breakdown.MethodsWe evaluated the differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top-ranked genes from networks and pathways were further evaluated with vascular injury traits.ResultsWe observed differentially expressed genes with P < 0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P < 3.3 × 10−6) within ε2/ε3 and ε3/ε4 groups, respectively. Gene set enrichment analysis revealed 21 significant pathways (false discovery rate P < 0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in subjects lacking ε4. We identified a co-expressed gene network in the brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated with at least one vascular injury trait.ConclusionThese results suggest that the APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4’s effect on the BBB.

Highlights

While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for the diagnosis and prediction of AD brain pathology
A post-mortem diagnosis of AD was established for 112 participants using National Institute on Aging (NIA)-Reagan criteria including Braak staging for assessing the severity of neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) semi-quantitative measure for neuritic plaques (CERAD score)
Of 78 genes containing or nearest to single nucleotide polymorphisms (SNPs) associated with AD at a genomewide significance level in a recent large genome-wide association study (GWAS) [41], 64 passed Quality control (QC) and were expressed in both brain and blood

Summary

Introduction

While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for the diagnosis and prediction of AD brain pathology. Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaques and neurofibrillary tau tangles in the brain [1]. Because these hallmark proteins are sometimes detectable in blood before clinical symptoms appear, there are on-going efforts to identify blood-based signatures from multiomics and biomarker data that can facilitate detection of AD preclinically [2, 3]. Cerebrovascular AD-related pathology that may affect the blood-brain barrier (BBB), such as cerebral amyloid angiopathy (CAA), has been shown to exacerbate neurodegeneration and neuroinflammation [6]. Cerebrovascular AD-related pathologies have shown APOE genotype-dependent patterns Both ε2 and ε4 are significantly associated with the risk of CAA [13]

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