Shared Causal Paths underlying Alzheimer’s dementia and Type 2 Diabetes

Abstract

Background: Although Alzheimer's disease (AD) is a central nervous system disease and type 2 diabetes mellitus (T2DM) is a metabolic disorder, an increasing number of genetic epidemiological studies show clear link between AD and T2DM. The current approach to uncovering the shared pathways between AD and T2DM involves association analysis; however, such analyses lack power to discover the mechanisms of the diseases. Methods:We develop novel statistical methods to shift the current paradigm of genetic analysis from association analysis to deep causal inference for uncovering the shared mechanisms between AD and T2DM, and develop pipelines to infer multilevel omics causal networks which lead to shifting the current paradigm of genetic analysis from genetic analysis alone to integrated causal genomic, epigenomic, transcriptional and phenotypic data analysis. To discover common causal paths from genetic variants to AD and T2DM, we also develop algorithms that can automatically search the causal paths from genetic variants to diseases and Results: The proposed methods and algorithms are applied to ROSMAP dataset with 432 individuals who simultaneously had genotype, RNA-seq, DNA methylation and some phenotypes. We construct multi-omics causal networks and identify 13 shared causal genes, 16 shared causal pathways between AD and T2DM, and 754 gene expression and 101 gene methylation nodes that were connected to both AD and T2DM in multi-omics causal networks. Conclusions:The results of application of the proposed pipelines for identifying causal paths to real data analysis of AD and T2DM provided strong evidence to support the link between AD and T2DM and unraveled causal mechanism to explain this link.

Transcriptional Profiling and Biological Pathway(s) Analysis of Type 2 Diabetes Mellitus in a Pakistani Population

“…ARNT is required to stimulate beta-cells to increase insulin production, and expression of the transcription factor of ARNT is reduced in the islets of humans with T2DM [48]. In our pilot study, the ARNT gene expression was upregulated (Figure 4,) and may have also triggered the down regulation of FOX01 and AKT with Insulin Receptor Signaling and Type 2 Diabetes Mellitus Signaling among the important canonical pathways (Figure 2), consistent with prior reports [49].…”

miR‑132 improves the cognitive function of rats with Alzheimer's disease by inhibiting the MAPK1 signal pathway

“…ERK is involved in cell activation and migration and plays an important role in synaptic plasticity and memory in vivo (38). Amyloid beta has been reported to induce JNK activation and cell death (39). Therefore, miR-132 may improve learning ability and memory, improving brain disorder in rats with AD and protecting nerve cells from apoptosis by inhibiting the p38 signaling pathway.…”

Type 3 Diabetes Mellitus: A Link Between Alzheimer's Disease and Type 2 Diabetes Mellitus

“…T2DM, another chronic disease, presents either as an absence of insulin most likely due to beta-cell burnout and/or insulin resistance. This may occur due to defective signaling at the cellular level, which may contribute to pancreatic burnout and hence the loss of glycemic controls [ 5 ]. The mechanism by which T2DM may involve the body is manifold.…”

“…Six phenotypes were found directly connected to the disease pathophysiology. Methylation can lead to variable gene expressions in the POU3F2, KIF4B, and TMSL3 within the dopaminergic synapses and adenosine monophosphate-activated protein kinase (AMPK) pathways leading to the genetic connection of both the diseases [ 5 ]. AMPK is known to be an energy modulator; it can stimulate the uptake of glucose in skeletal muscles and the catabolic effect of fatty acids in the adipose tissues by insulin sensitization.…”