Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer’s Disease: Evolutionary Features and Opportunities for Drug Repurposing

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelop-mental and neurodegenerative disorders respectively. While exome sequencing is rou-tinely employed during the early stages of ASD diagnosis, it rarely influences thera-peutic strategies. To address this gap we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signal-ing. In addition, we performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) values dis-tributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having ex-tremely low DI = 0 was found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using ANDVisio tool, both pharmacological and natu-ral mTOR regulators with potential for ASD treatment were selected such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol and several amino acids.