A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease
Artikel i vetenskaplig tidskrift, 2012

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.

excitatory synapses


synaptic plasticity


cognitive impairment




cytoskeleton-associated protein

immediate-early gene


Sara Landgren

Göteborgs universitet

Malin von Otter

Göteborgs universitet

Mona Seibt Palmer

Göteborgs universitet

Caroline Zetterstrom

Göteborgs universitet

Staffan Nilsson

Göteborgs universitet

Chalmers, Matematiska vetenskaper, Matematisk statistik

Ingmar Skoog

Göteborgs universitet

Deborah Gustafson

Göteborgs universitet

L. Minthon

Lunds universitet

Anders Wallin

Göteborgs universitet

Niels Andreasen

Karolinska Institutet

Nenad Bogdanovic

Karolinska Institutet

Jan Marcusson

Linköpings universitet

Kaj Blennow

Göteborgs universitet

Henrik Zetterberg

Göteborgs universitet

University College London (UCL)

Petronella Kettunen

Göteborgs universitet

Journal of Neural Transmission

03009564 (ISSN) 14351463 (eISSN)

Vol. 119 7 833-842





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