A Continuous Extension of Gene Set Enrichment Analysis using the Likelihood Ratio Test Statistics Identifies VEGF as a Candidate Pathway for Alzheimers disease

BackgroundAlzheimers disease involves brain pathologies such as amyloid plaque depositions and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand the disease etiology and devise therapies. ObjectiveOur objective was to identify molecular pathways associated with AD biomarkers (Amyloid-{beta} and tau) and cognitive status (MMSE) accounting for variables such as age, sex, education, and APOE genotype. MethodsWe introduce a novel pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (Amyloid-{beta}, tau, cognition), using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved a large sample size with data available for all three phenotypes, allowing for the identification of common pathways. ResultsWe identified 14 pathways significantly associated with Amyloid-{beta}, 5 associated with tau, and 174 associated with MMSE. Surprisingly, the MMSE outcome showed a larger number of significant pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited significant associations with all three phenotypes. ConclusionsThe studys findings highlight the importance of the VEGF signaling pathway in aging in AD. The complex interactions within the VEGF signaling family offer valuable insights for future therapeutic interventions.