New insights into the genetic etiology of Alzheimer’s disease and related dementias
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Abstract
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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The record
- Venue
- Nature Genetics
- Topic
- Genetic Associations and Epidemiology
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Université de MontréalCentre Hospitalier Universitaire Sainte-JustineHospital for Sick ChildrenOccupational Cancer Research CentreSickKids FoundationUniversity of Toronto
- Funders
- National Institute on Minority Health and Health DisparitiesNational Institute of Neurological Disorders and StrokeRheinische Friedrich-Wilhelms-Universität BonnUniversitat de BarcelonaNational Heart, Lung, and Blood InstituteCentro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas AsociadasDeutsches Zentrum für Neurodegenerative ErkrankungenMotor Neurone Disease AssociationNational Institute on AgingNational Institute for Health and Care ResearchUniversität zu KölnNational and Kapodistrian University of AthensMcLean HospitalUniversité de LilleUniversity of WashingtonRégion NormandieHarokopio UniversityHoward Hughes Medical InstituteDevelopment of Innovative Strategies for a Transdisciplinary approach to ALZheimer's diseaseUniversität Duisburg-EssenAgence Nationale de la RechercheBiotechnology and Biological Sciences Research CouncilWellcome TrustSchool of Medicine, Boston UniversityLundbeckfondenInstitut National de la Santé et de la Recherche MédicaleUniversità degli Studi di CagliariMedical Research Council
- Keywords
- BiologyEtiologyDiseaseAlzheimer's diseaseGeneticsBioinformaticsPathologyMedicine
- Has abstract in OpenAlex
- yes