Profiling of Specific Gene Expression Pathways in Peripheral Cells from Prodromal Alzheimer’s Disease Patients

Transcriptome–wide association studies (TWAS) have identified several genes that are associated with qualitative traits. In this work, we performed TWAS using quantitative traits and predicted gene expressions in six brain subcortical structures in 286 mild cognitive impairment (MCI) samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The six brain subcortical structures were in the limbic region, basal ganglia region, and cerebellum region. We identified 9, 15, and 6 genes that were stably correlated longitudinally with quantitative traits in these three regions, of which 3, 8, and 6 genes have not been reported in previous Alzheimer’s disease (AD) or MCI studies. These genes are potential drug targets for the treatment of early–stage AD. Single–Nucleotide Polymorphism (SNP) analysis results indicated that cis–expression Quantitative Trait Loci (cis–eQTL) SNPs with gene expression predictive abilities may affect the expression of their corresponding genes by specific binding to transcription factors or by modulating promoter and enhancer activities. Further, baseline structure volumes and cis–eQTL SNPs from correlated genes in each region were used to predict the conversion risk of MCI patients. Our results showed that limbic volumes and cis–eQTL SNPs of correlated genes in the limbic region have effective predictive abilities.

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Disturbance of phylogenetic layer-specific adaptation of human brain gene expression in Alzheimer's disease

Scientific Reports ◽

10.1038/s41598-021-99760-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Natasha Andressa Nogueira Jorge ◽

Uwe Ueberham ◽

Mara Knobloch ◽

Peter F. Stadler ◽

Jörg Fallmann ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Neurodegenerative Disorder ◽

Critical Role ◽

Subcortical White Matter ◽

Specific Gene ◽

Specific Adaptation ◽

Vesicle Exocytosis

AbstractAlzheimer's disease (AD) is a progressive neurodegenerative disorder with typical neuropathological hallmarks, such as neuritic plaques and neurofibrillary tangles, preferentially found at layers III and V. The distribution of both hallmarks provides the basis for the staging of AD, following a hierarchical pattern throughout the cerebral cortex. To unravel the background of this layer-specific vulnerability, we evaluated differential gene expression of supragranular and infragranular layers and subcortical white matter in both healthy controls and AD patients. We identified AD-associated layer-specific differences involving protein-coding and non-coding sequences, most of those present in the subcortical white matter, thus indicating a critical role for long axons and oligodendrocytes in AD pathomechanism. In addition, GO analysis identified networks containing synaptic vesicle transport, vesicle exocytosis and regulation of neurotransmitter levels. Numerous AD-associated layer-specifically expressed genes were previously reported to undergo layer-specific switches in recent hominid brain evolution between layers V and III, i.e., those layers that are most vulnerable to AD pathology. Against the background of our previous finding of accelerated evolution of AD-specific gene expression, here we suggest a critical role in AD pathomechanism for this phylogenetic layer-specific adaptation of gene expression, which is most prominently seen in the white matter compartment.

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