![]() As a proof‐of‐concept alongside APOE, which is the locus consistently associated with longevity across different populations (Abondio et al., 2019), several other LOAD‐associated loci were found to affect the human lifespan (Tesi et al., 2021). ![]() Interestingly, many of these mechanisms are common to human longevity, suggesting that the search of susceptibility factors could be enhanced by testing genes belonging to pathways influencing longevity and survival. Such variants may be found in the underlying processes leading to LOAD, such as inflammation (Akiyama et al., 2000), apoptosis (Behl, 2000), stress response (Iatrou et al., 2021), and mitochondrial decay (Kwong et al., 2006). While advances in technologies and increased availability of multi‐omics data have expanded our knowledge about LOAD genetic architecture, many risk variants remain to be identified (Andrews et al., 2023). These epistatic effects may contribute substantially to the variation in disease susceptibility that is, people carrying risk factors for LOAD but resilient to the disease, as well as people carrying the risk allele APOE*4 who live into their 90s without developing dementia. In the interactome network of the cell, each variant may show different effects (either in magnitude or in direction) on disease onset, in relation to alleles at other loci (Ridge et al., 2016). Also, functional genomic analyses pointed out that common LOAD risk variants operate in complex networks of genetic and metabolic interactions, regulated by “hub” genes and “peripheral master regulators” (Gui et al., 2021). Genetic studies over the last few years, particularly coming from genome‐wide association studies (GWAS) and large sequencing projects, have changed the perception of LOAD, highlighting its polygenic nature with multiple susceptibility genetic loci (Andrews et al., 2023). A current challenge is to clarify the contribution of genetic, epigenetic, and environmental factors in the multifactorial nature of LOAD, which shows a heritability of 58%–79%, with a large fraction attributable to the APOE locus. Decades of research have shed light on the neuropathological changes happening in the AD brain, and its complex etiology (Long & Holtzman, 2019), characterized by sex differences in several aspects of the disease, including its onset and progression, and the effects of APOE*4 genotype, the strongest common genetic risk factor for LOAD (Nebel et al., 2018). Most AD cases are sporadic or late onset (LOAD >65 years of age), with biological measures of disease being detectable as early as 20 years before the first cognitive symptoms are observed (Jagust, 2018). 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.Īlzheimer's disease (AD) is the most prevalent disease among people over 85 years of age in western countries, posing a significant challenge to public health systems around the world. ![]() These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. 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. Furthermore, interacting variants associated with LOAD in a sex‐ and APOE‐specific way. Among the significantly interacting genes, PTPN1, TXNRD1, and IGF1R were already found enriched in gene–gene interactions affecting survival to old age. The stratified analysis according to APOE*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. ![]() 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). 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. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. 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.
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