Polygenic hazard score predicts synaptic and axonal degeneration and cognitive decline in Alzheimer's disease continuum.

BACKGROUND: Growth associated protein-43 (GAP-43) and neurofilaments light (NFL) are biomarkers of synaptic and axonal injury, and are associated with cognitive decline in Alzheimer's disease (AD) contiuum. We investigated whether Polygenic Hazard Score (PHS) is associated with specific biomarkers and cognitive measures, and if it can predict the relationship between GAP-43, NFL, and cognitive decline in AD. METHOD: We enrolled 646 subjects: 93 with AD, 350 with mild cognitive impairment (MCI), and 203 cognitively normal controls. Variables included GAP-43, plasma NFL, and PHS. A PHS of 0.21 or higher was considered high risk while a PHS below this threshold was considered low risk. A subsample of 190 patients with MCI with four years of follow-up cognitive assessments were selected for longitudinal analysis . We assessed the association of the PHS with AD biomarkers and cognitive measures, as well as the predictive power of PHS on cognitive decline and the conversion of MCI to AD. RESULTS: PHS showed high diagnostic accuracy in distinguishing AD, MCI, and controls. At each follow-up point, high risk MCI patients showed higher level of cognitive impairment compared to the low risk group. GAP-43 correlated with all follow-up cognitive tests in high risk MCI patients which was not detected in low risk MCI patients. Moreover, high risk MCI patients progressed to dementia more rapidly compared to low risk patients. CONCLUSION: PHS can predict cognitive decline and impacts the relationship between neurodegenerative biomarkers and cognitive impairment in AD contiuum. Categorizing patients based on PHS can improve the prediction of cognitive outcomes and disease progression.

Analyzing alternative splicing in Alzheimer's disease postmortem brain: a cell-level perspective.

Alzheimer's disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain's cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including CLU in astrocytes and excitatory neurons, PTGDS in astrocytes and endothelial cells, and HSP90AA1 in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor DDX5. In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as MEG3 in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes.

miR-298 plays a pivotal role in colon cancer invasiveness by targeting PTEN.

Evidence indicate that the miR-298 dysregulation might associate with colorectal cancer (CRC) development. Herein, we evaluated the effect of miR-298 dysregulation on colon cancer invasiveness. First, metabolic activity, cell cycle progression, apoptosis, and invasion of miR-298 overexpressed/knocked out colon cancer cells were examined and combined with their transcriptome analysis data for better visualization of miR-298 intracellular signaling networks. Interaction between miR-298 and its target was evaluated with luciferase assay and validated using western blot analysis. The proportion of abnormal miR-298 level was investigated in tumor samples, matched normal adjacent tissues, and plasmas of 100 CRC patients, and also compared with 100 normal plasma samples. The Mann-Whitney U test was performed to assess miR-298 differences among the studied groups, and the correlation between miR-298 and the risk of CRC was shown by univariate and multivariate logistic regression. The data indicate that miR-298 overexpression promoted proliferation and metastasis in CRC cells via targeting phosphatase and tensin homolog. Comparative analysis of CRC tumors, normal adjacent tissues, and plasmas indicated a significant miR-298 upregulation in tumors and plasmas (1.72-fold and 1.65-fold, respectively; p < .001). Also, the aberrant level of miR-298 contributed with CRC tumor differentiation, TNM stage and lymph node metastasis (p < .001), and independently associated with poor survival of CRC patients (p < .029; hazard ratio: 1.292; 95% confidence interval: 0.339-2.184). Collectively, these data showed that abnormal level of miR-298 correlated with cancer development and through that lowered the overall survival rate of CRC patients. Therefore, miR-298 could be considered as a therapeutic target for CRC.