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Mol Neurobiol. 2019 Oct 29. doi: 10.1007/s12035-019-01798-0. [Epub ahead of print]

Familial Alzheimer's Disease and Recessive Modifiers.

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Universidad del Norte, Barranquilla, Colombia.
Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
INPAC Research Group, Fundación Universitaria Sanitas, Bogotá, Colombia.
Grupo de Investigación en Psiquiatría (GIPSI), Departamento de Psiquiatría, Instituto de Investigaciones Médicas (IIM), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.


Alzheimer's disease (AD) is progressive brain disorder that affects ~ 50 million people worldwide and has no current effective treatment. AD age of onset (ADAOO) has shown to be critical for the identification of genes that modify the appearance of AD signs and symptoms in a specific population. We clinically characterized and whole-exome genotyped 71 individuals with AD from the Paisa genetic isolate, segregating the (PSEN1) E280A dominant fully penetrant mutation, and analyzed the potential recessive effects of ~ 50,000 common functional genomic variants to the ADAOO. Standard quality control and filtering procedures were applied, and recessive single- and multi-locus linear mixed-effects models were used. We identified genetic variants in the SLC9C1, CSN1S1, and LOXL4 acting recessively to delay ADAOO up to ~ 11, ~ 6, and ~ 9 years on average, respectively. In contrast, the CC recessive genotype in marker DHRS4L2-rs2273946 accelerates ADAOO by ~ 8 years. This study, reports new recessive variants modifying ADAOO in PSEN1 E280A mutation carriers. This set of genes are implicated in important biological processes and molecular functions commonly affected by genes associated with the etiology of AD such as APP, APOE, and CLU. Future functional studies using modern techniques such as induced pluripotent stem cells will allow a better understanding of the over expression and down regulation of these recessive modifier variants and hence the pathogenesis of AD. These results are important for prediction of AD and ultimately, substantial to develop new therapeutic strategies for individuals at risk or affected by AD.


Age of onset; Alzheimer’s disease; Genetic Interactions; Genetic Isolates; PSEN1; Recessive Mutations


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