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Calero M, Gómez-Ramos A, Calero O, et al. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease. Front Cell Neurosci. 2015;9:138doi: 10.3389/fncel.2015.00138.
Calero, M., Gómez-Ramos, A., Calero, O., Soriano, E., Avila, J., & Medina, M. (2015). Additional mechanisms conferring genetic susceptibility to Alzheimer's disease. Frontiers in cellular neuroscience, 9138. https://doi.org/10.3389/fncel.2015.00138
Calero, Miguel, et al. "Additional mechanisms conferring genetic susceptibility to Alzheimer's disease." Frontiers in cellular neuroscience vol. 9 (2015): 138. doi: https://doi.org/10.3389/fncel.2015.00138
Calero M, Gómez-Ramos A, Calero O, Soriano E, Avila J, Medina M. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease. Front Cell Neurosci. 2015 Apr 09;9:138. doi: 10.3389/fncel.2015.00138. eCollection 2015. PMID: 25914626; PMCID: PMC4391239.
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Front Cell Neurosci. 2015 Apr 09;9:138. doi: 10.3389/fncel.2015.00138. eCollection 2015.

Additional mechanisms conferring genetic susceptibility to Alzheimer's disease.

Frontiers in cellular neuroscience

Miguel Calero, Alberto Gómez-Ramos, Olga Calero, Eduardo Soriano, Jesús Avila, Miguel Medina

Affiliations

  1. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Madrid, Spain ; Chronic Disease Programme, Instituto de Salud Carlos III Madrid, Spain ; Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center Madrid, Spain.
  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Madrid, Spain ; Centro de Biología Molecular Severo Ochoa CSIC-UAM Madrid, Spain.
  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Madrid, Spain ; Chronic Disease Programme, Instituto de Salud Carlos III Madrid, Spain.
  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Madrid, Spain ; University of Barcelona Barcelona, Spain.
  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Madrid, Spain ; Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center Madrid, Spain.

PMID: 25914626 PMCID: PMC4391239 DOI: 10.3389/fncel.2015.00138

Abstract

Familial Alzheimer's disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid β peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR∼4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes.

Keywords: Alzheimer; GWAS; epistasis; exome; neurodegeneration; rare variants; risk factors; somatic mutations

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