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Neurobiol Aging. 2015 Mar;36(3):1605.e13-20. doi: 10.1016/j.neurobiolaging.2014.12.007. Epub 2014 Dec 11.

Influence of genetic variants in SORL1 gene on the manifestation of Alzheimer's disease.

Author information

1
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: e.louwersheimer@vumc.nl.
2
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany.
3
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
4
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
5
Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen, Nuremberg, Germany.
6
Department of Psychiatry, Charite, Berlin, Germany.
7
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
8
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
9
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
10
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; Department of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.
11
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
12
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
13
Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands.
14
Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
15
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
16
Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands; Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.

Abstract

We studied the association of SORL1 single-nucleotide polymorphisms genotypes with measures of pathology in patients with probable Alzheimer's disease (AD) using an endophenotype approach. We included (1) 133 patients from the German Dementia Competence Network (71 ± 8 years; 50% females; Mini Mental State Examination [MMSE], 24 ± 3); (2) 83 patients from the Alzheimer's Disease Neuroimaging Initiative (75 ± 8 years; 45% females; MMSE, 24 ± 2); and (3) 452 patients from the Amsterdam Dementia Cohort 66 ± 8 years; 47% females; MMSE, 20 ± 5). As endophenotype markers we used cognitive tests, cerebrospinal fluid (CSF) biomarkers amyloid-beta, total tau (tau), tau phosphorylated at threonine 181, and hippocampal atrophy. We measured 19 SORL1 SNP alleles. Genotype-endophenotype associations were determined by linear regression analyses. There was an association between rs2070045-G allele and increased CSF-tau and more hippocampal atrophy. Additionally, haplotype-based analyses revealed an association between haplotype rs11218340-A/rs3824966-G/rs3824968-A and higher CSF-tau and CSF-tau phosphorylated at threonine 181. In conclusion, we found that SORL1 SNP rs2070045-G allele was related to CSF-tau and hippocampal atrophy, 2 endophenotype markers of AD, suggesting that SORL1 may be implicated in the downstream pathology in AD.

KEYWORDS:

Alzheimer's disease; Endophenotypes; SNPs; SORL1

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