Genetic Study of Neurexin and Neuroligin Genes in Alzheimer's Disease
Abstract
The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males.
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NRXN3 is the isoform most consistently implicated in AD pathogenesis.
“given that this isoform has been most consistently implicated in AD pathogenesis35–39.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [35]
Cites
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Sex differences in the genetic architecture of Alzheimer’s disease
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“To strengthen the potential implication of neurexins, we selected NRXN3 for further validation, given that this isoform has been most consistently implicated in AD pathogenesis 35–39 .”
- Authors
- Martinez-Mir, A., Initiative, A. D. N., González-Pérez, A., Gayán, J., Antúnez, C., Marín, J., Boada, M., Lopez-Arrieta, J. M., Fernández, E., Ramírez-Lorca, R., Sáez, M. E., Ruiz, A., Scholl, F. G., & Real, L. M.
- Affiliations
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain
- Departamento de Genómica Estructural, Neocodex, Sevilla, Spain
- Hospital Universitario Virgen de la Arrixaca (ES)
- Universitat Autònoma de Barcelona (ES)
- Fundació ACE. Barcelona Alzheimer Treatment & Reserch Center, Barcelona, Spain
- Unidad de Memoria, Hospital Universitario La Paz-Cantoblanco, Madrid, Spain
- Fundació ACE (ES)
- Instituto de Biomedicina de Sevilla (ES)
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2013-04-17
- Volume
- 35
- Issue
- 2
- Pages
- 403-412
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1587357266
- Cited by
- 45
- References
- 7
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 3
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Corporación Tecnológica de Andalucía
- National Institute on Aging
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, neurexin
- MeSH terms
- Alzheimer Disease, Calcium-Binding Proteins, DNA, Genetic Markers, Genotype, Haplotypes, Humans, Nerve Tissue Proteins, Sex Characteristics, Spain, Linkage Disequilibrium, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Polymorphism, Single Nucleotide, Databases, Genetic, White People, Genome-Wide Association Study
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