Effects of copy number variations on longevity in late-onset Alzheimer’s disease patients: insights from a causality network analysis

Abstract

Alzheimer’s disease (AD), particularly late-onset Alzheimer’s disease (LOAD), is a prevalent form of dementia that significantly affects patients’ cognitive and behavioral capacities and longevity. Although approximately 70 genetic risk factors linked with AD have been identified, their influence on patient longevity remains unclear. Further, recent studies have associated copy number variations (CNVs) with the longevity of healthy individuals and immune-related pathways in AD patients. This study aims to investigate the role of CNVs on the longevity of AD patients by integrating the Whole Genome Sequencing (WGS) and transcriptomics data from the Religious Orders Study/Memory and Aging Project (ROSMAP) cohort through causality network inference. Our comprehensive analysis led to the construction of a CNV-Gene-Age of Death (AOD) causality network. We successfully identified three key CNVs (DEL5006, mCNV14192, and DUP42180) and seven AD-longevity causal genes (PLGRKT, TLR1, PLAU, CALB2, SYTL2, OTOF, and NT5DC1) impacting AD patient longevity, independent of disease severity. This outcome emphasizes the potential role of plasminogen activation and chemotaxis in longevity. We propose several hypotheses regarding the role of identified CNVs and the plasminogen system on patient longevity. However, experimental validation is required to further corroborate these findings and uncover precise mechanisms. Despite these limitations, our study offers promising insights into the genetic influence on AD patient longevity and contributes to paving the way for potential therapeutic interventions.