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 neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have 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) value distributions 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 extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural 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.