Computational Modelling and Clinical Validation of an Alzheimer's-Related Network in Brain Cancer: The SKM034 Model

Cancer and Alzheimer's disease (AD) display an inverse relationship, and there is a need to further explore this interplay. One key genetic contributor to AD is SORL1, the loss of which is thought to be causally related to AD development. SORL1 also appears to be implicated in cancer. To examine SORL1 and its network, this article simulated SORL1 and its interactions via signal-flow Boolean modelling, including in silico knockouts (mirroring in vivo loss-of-function mutations). This model (SKM034) predicted a total of 29 key changes in molecular relationships following the loss of SORL1 or another highly connected protein (ERBB2). Literature validation demonstrated that 2 of these predictions were at least partially validated experimentally, whilst 27 were Potentially Novel Predictions (PNPs). Complementing the in-depth relationship analyses was signal flow analysis through the network's structure, validated using cell line and cancer patient RNA-seq data. Correct prediction rates for these analyses reached 60% (statistically significant relative to a random model). This article demonstrates the clinical relevance of this Alzheimer's-related network in a cancer context and, through the PNPs, provides a strong starting point for in vitro experimental validation. As with previously published models using similar methods, the model may be reanalysed in different contexts for further discoveries.