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. 2023 Sep;22(9):e13938.
doi: 10.1111/acel.13938. Epub 2023 Aug 24.

Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene-gene interaction of longevity-related loci

Serena Dato  1 , Francesco De Rango  1 , Paolina Crocco  1 , Stefano Pallotti  2 , Michael E Belloy  3 , Yann Le Guen  3 , Michael D Greicius  3 , Giuseppe Passarino  1 , Giuseppina Rose  1 , Valerio Napolioni  2
Affiliations

Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene-gene interaction of longevity-related loci

Serena Dato et al. Aging Cell. 2023 Sep.

Abstract

Advanced age is the largest risk factor for late-onset Alzheimer's disease (LOAD), a disease in which susceptibility correlates to almost all hallmarks of aging. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene-gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to APOE*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, PTPN1, TXNRD1, and IGF1R were already found enriched in gene-gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex- and APOE-specific way. Indeed, while in APOE*4 female carriers we found several inter-pathway interactions, no significant epistasis was found in APOE*4 negative females; conversely, in males, significant intra- and inter-pathways epistasis emerged according to APOE*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex- and APOE-stratified preventive and therapeutic interventions for LOAD.

Keywords: Alzheimer's Disease; IGF1; epistasis; gene-gene interaction; longevity; polymorphism.

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Conflict of interest statement

The authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
Flowchart describing the steps of the analysis after quality control and filtering.
FIGURE 2
FIGURE 2
VENN diagram built on Table S1 data, showing the number of variants associated with LOAD in each sub‐group of samples and in common between different groups.
FIGURE 3
FIGURE 3
Schematic representation of gene‐based analysis, reporting the top‐genes (p < 0.01) associated with the disease in each different sub‐group and those shared. Colors represent the three analyzed pathways.
FIGURE 4
FIGURE 4
Interaction graphs, reporting the significant markers from MDR analysis, in the group of APOE*4+ females (a), in APOE*4− females, in APOE*4+ males, and in APOE*4− males (d). For each variant we reported the value of information gain (IG) in per cent, while numbers in the connections indicate the entropy‐based IG for the variant pairs. Red bar and orange bar indicate the high‐level synergies on the phenotype, while the brown indicate a medium‐level interaction, green and blue connections with negative IG values indicate redundancy or lack of synergistic interactions between the markers.
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References

    1. 1000 Genomes Project Consortium , Auton, A. , Brooks, L. D. , Durbin, R. M. , Garrison, E. P. , Kang, H. M. , Korbel, J. O. , Marchini, J. L. , McCarthy, S. , McVean, G. A. , & Abecasis, G. R. (2015). A global reference for human genetic variation. Nature, 526(7571), 68–74. 10.1038/nature15393 - DOI - PMC - PubMed
    1. Abondio, P. , Sazzini, M. , Garagnani, P. , Boattini, A. , Monti, D. , Franceschi, C. , Luiselli, D. , & Giuliani, C. (2019). The Genetic variability of APOE in different human populations and its implications for longevity. Genes, 10(3), 222. 10.3390/genes10030222 - DOI - PMC - PubMed
    1. Akhtar, A. , & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer's disease. Neurochemistry International, 135, 104707. 10.1016/j.neuint.2020.104707 - DOI - PubMed
    1. Akiyama, H. , Barger, S. , Barnum, S. , Bradt, B. , Bauer, J. , Cole, G. M. , Cooper, N. R. , Eikelenboom, P. , Emmerling, M. , Fiebich, B. L. , Finch, C. E. , Frautschy, S. , Griffin, W. S. , Hampel, H. , Hull, M. , Landreth, G. , Lue, L. , Mrak, R. , Mackenzie, I. R. , … Wyss‐Coray, T. (2000). Inflammation and Alzheimer's disease. Neurobiology of Aging, 21(3), 383–421. 10.1016/s0197-4580(00)00124-x - DOI - PMC - PubMed
    1. Andrews, S. J. , Renton, A. E. , Fulton‐Howard, B. , Podlesny‐Drabiniok, A. , Marcora, E. , & Goate, A. M. (2023). The complex genetic architecture of Alzheimer's disease: Novel insights and future directions. eBioMedicine, 90, 104511. 10.1016/j.ebiom.2023.104511 - DOI - PMC - PubMed

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