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Genetic drivers of longevity provide protection against Alzheimer's disease pathology
Author(s) -
Riedel Brandalyn C.,
Dumitrescu Logan,
Hohman Timothy J.,
Saykin Andrew J.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045570
Subject(s) - longevity , genome wide association study , biology , apolipoprotein e , pleiotropy , allele , genetic association , genetics , disease , gene , single nucleotide polymorphism , medicine , pathology , phenotype , genotype
Background Genome‐wide association studies (GWAS) have consistently found human longevity correlations within the APOE gene cluster ( APOE , APOC1 , TOMM40 , PVRL2 ). Many variants in this cluster show inverse effects between longevity and Alzheimer’s disease (AD). This suggests genetic pleiotropy between AD and longevity, e.g., the APOE ε2 allele is associated with both protection from AD and increased longevity. Recent evidence supports the idea that certain aged individuals do not have significant AD pathology, exhibiting AD resistance. Here we sought to determine whether a genetic signal of AD resistance could be identified by leveraging previous GWAS of longevity and AD pathology. Method We used a large meta‐analysis of longevity, defined as reaching the 90th age percentile for a birth cohort compared to those who reach the 60th. Following p‐value informed LD‐clumping (r2 ≥ 0.1), we used random‐effects regression to meta‐analyze three GWAS on AD phenotypes: cerebrospinal fluid levels of amyloid, and phosphorylated tau, as well as amyloid PET imaging. Subsequent methods are shown in Figure 1 and involved mapping variants to genes and determining gene scores and pathway enrichment using PASCAL. Results Variants showing discordant effects between AD pathology and longevity (increased pathology/decreased longevity or decreased pathology/increased longevity) included APOE and others across the genome. The top Reactome pathways (p < 0.05) included those involved in axon growth and guidance (Signal transduction and recycling by L1, signalling of NGF, Neurotrophin signalling), cell survival and apoptosis (MAPK pathway, ERK/MAPK targets, NFKB/MAPK activation by TLR4), lipid metabolism (chylomicron‐mediated and HDL‐mediated lipid transport), and the immune system (innate and adaptive). Conclusion Significant pleiotropy exists between longevity and AD pathology, implying that focus on discordant effects may yield novel insights relevant to AD resistance. Ongoing work seeks to map results from our discordance analysis to an AD‐specific transcriptional regulatory network created from the Harvard Brain Tissue Resource Center data, with hubs of known transcription factors. This will allow identification of functional modules via eQTL enrichment, will help to further characterize these effects, and may prove useful for downstream drug repurposing analyses.