Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

Abstract

Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

Non‐coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women

“…We note a recent AD GWAS identified significant associations unique to those with or without hypertension, 47 suggesting that GWAS stratified by different AD risk factors may find novel results. Similarly, recent studies highlight shared genetic architecture and pathways between AD and other causes of dementia; 4,5 GWAS for dementia as defined in our study may enrich for those features shared across causes of dementia rather than those specific to AD. The WHI cohort is also exclusively female.…”

“…DEGs from a study of single‐cell RNA‐seq data collected from three groups of ROS samples, those with little to no AD pathology, early‐stage AD pathology, or late‐stage AD pathology (N = 48), 24 were defined by an FDR‐adjusted P < .01 and absolute log 2 fold change (log 2 FC) > 0.25. Expression microarray data from the frontal cortex were used to identify DEGs for AD, vascular dementia (VaD), and FTD versus controls (N = 140), 5 with DEGs defined as those with a log 2 FC ≥1.2 and P ≤ .05. Additional details for each of these studies are provided in Supplemental Methods.…”

“…This may be because GWAS are typically underpowered for detecting associations with rare variants. Dementia also exhibits considerable phenotypic heterogeneity, and it is often difficult to distinguishing AD from vascular or other subtypes of dementia 4–6 …”

“…Dementia also exhibits considerable phenotypic heterogeneity, and it is often difficult to distinguishing AD from vascular or other subtypes of dementia. [4][5][6] There is a complex relationship between vascular risk factors and dementia. Both AD and cerebrovascular disease increase in prevalence with age and share risk factors like hypertension, APOE genotype, smoking, and diabetes mellitus.…”

Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease

“…This approach has been very successful in harmonizing the analysis of different studies, by allowing the use of large sample numbers and thereby permitting the identification of novel markers for various diseases ( 14 – 16 ). New associations between different pathologies such as infection and autoimmunity have also been found through such approaches ( 17 – 19 ). Combining genomic and transcriptomic analyses can help better understand the molecular pathways and processes associated with H. pylori infection and define disease signatures associated with different stages of disease development.…”