title: A Genetic Variant of the Sortilin 1 Gene is Associated with Reduced Risk of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Andersson
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.|Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Sweden.|Memory Clinic, Skåne University Hospital, Malmö, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Skoog
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Wallin
authors.affiliation: Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Neuropathology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Petronella
authors.initials: P
authors.lastname: Kettunen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D016022:Case-Control Studies; D060467:Disease Resistance / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D060005:Genotyping Techniques; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D000073216:Mental Status and Dementia Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013548:Sweden; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D010446:Peptide Fragments; D000099183:Sortilin; C075222:amyloid beta-protein (1-42)
keywords: Amyloid beta-peptides; apolipoprotein E; biomarkers; genetic association studies; genotype; neuropsychological tests; risk factors; single nucleotide polymorphism; tau proteins; vesicular transport adaptor proteins