Abstract
There is an urgent need to identify biomarkers for Alzheimer’s disease (AD), but the identification of reliable blood-based biomarkers has proven to be much more difficult than initially expected. The current availability of high-throughput multi-omics data opens new possibilities in this titanic task. Candidate Single Nucleotide Polymorphisms (SNPs) from large, genome-wide association studies (GWAS), meta-analyses exploring AD (case-control design), and quantitative measures for cortical structure and general cognitive performance were selected. The Genotype-Tissue Expression (GTEx) database was used for identifying expression quantitative trait loci (eQTls) among candidate SNPs. Genes significantly regulated by candidate SNPs were investigated for differential expression in AD cases versus controls in the brain and plasma, both at the mRNA and protein level. This approach allowed us to identify candidate susceptibility factors and biomarkers of AD, facing experimental validation with more evidence than with genetics alone.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia worldwide, affecting36 million people nowadays, and it is expected to triple its prevalence by mid-century.Familial forms of AD are caused by mutations on the amyloid-related genes PSEN1, PSEN2, and APP, while diverse candidate genes and pathways have been reported for sporadicAD, mainly provided by genome-wide association studies (GWAS) [1,2,3,4,5,6,7]
Genes regulated in diverse brain tissues by the 2186th, 398th, and 412th candidate SNPs from AD, cognition, and cortical measures GWAS were explored using GenotypeTissue Expression (GTEx)
AD and cortical measures Expression Quantitative Trait Loci (eQTL)-regulated gene lists, whereas 24 shared genes were identified for the cognitive performance and cortical structure phenotypes (ARHGAP27, ARL17A, DCC, DEPDC1B, FMNL1, GOSR1, KANSL1, KANSL1-AS1, LINC02210, LOC107984142, LOC339192, LRRC37A, LRRC37A2, MAPT, NDUFAF2, NPIPB9, PLEKHM1, RPS26, SH2B1, SPPL2C, SULT1A1, SULT1A2, SUOX, and TUFM)
Summary
Alzheimer’s disease (AD) is the leading cause of dementia worldwide, affecting36 million people nowadays, and it is expected to triple its prevalence by mid-century.Familial forms of AD are caused by mutations on the amyloid-related genes PSEN1, PSEN2, and APP, while diverse candidate genes and pathways have been reported for sporadicAD, mainly provided by genome-wide association studies (GWAS) [1,2,3,4,5,6,7]. The largest risk factor for AD identified so far is the apolipoprotein E (APOE)E4 allele, conferring up to. The clinical major hallmarks of AD are amyloid deposits and neurofibrillary tangles. With this observation, amyloid, tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) have been found to be present at low levels in the cerebrospinal fluid (CSF) of AD patients when compared to controls, being the only AD biomarkers currently employed in the clinical setting [8,9,10]. Considerable efforts have been put into identifying biomarkers of the disease, especially in the prodromal stage, when early intervention is expected to reduce the burden of the disease. Diverse CSF biomarkers have been proposed, including the neurofilament light protein (NFL) [11], neurogranin (Ng) [12], the neuron-specific enolase (NSE) [13], the visinin-like protein 1
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