TY - JOUR

T1 - Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer’s Disease: Evolutionary Features and Opportunities for Drug Repurposing

AU - Trifonova, Ekaterina A.

AU - Pashchenko, Anna A.

AU - Ivanov, Roman A.

AU - Kochetov, Alex V.

AU - Lashin, Sergey A.

N1 - This research was funded by Budget Project #FWNR-2025-0018 of the Ministry of Science and Higher Education of The Russian Federation. Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer’s Disease: Evolutionary Features and Opportunities for Drug Repurposing / E. A. Trifonova, A. A. Pashchenko, R. A. Ivanov, A. V. Kochetov, S. A. Lashin // International Journal of Molecular Sciences. – 2025. – Vol. 26, No. 20. – С. 10066. DOI 10.3390/ijms262010066

PY - 2025/10/16

Y1 - 2025/10/16

N2 - 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.

AB - 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.

KW - genetics

KW - Bioinformatics

KW - autism spectrum disorder (ASD)

KW - Alzheimer’s disease

KW - mTOR signaling pathway

KW - Phylostratigraphic Age Index (PAI)

KW - Divergence Index (DI)

KW - drug repurposing

UR - https://www.mdpi.com/1422-0067/26/20/10066

UR - https://www.mendeley.com/catalogue/fc239fa5-149e-39df-b35b-33d77d5619a9/

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105020272431&origin=inward

U2 - 10.3390/ijms262010066

DO - 10.3390/ijms262010066

M3 - Article

C2 - 41155356

VL - 26

SP - 10066

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 20

ER -