Journal of Neural Transmission

, Volume 119, Issue 7, pp 833–842

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

  • Sara Landgren
  • Malin von Otter
  • Mona Seibt Palmér
  • Caroline Zetterström
  • Staffan Nilsson
  • Ingmar Skoog
  • Deborah R. Gustafson
  • Lennart Minthon
  • Anders Wallin
  • Niels Andreasen
  • Nenad Bogdanovic
  • Jan Marcusson
  • Kaj Blennow
  • Henrik Zetterberg
  • Petronella Kettunen
Dementias - Original Article

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) 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 Aβ 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-tau181) and Aβ1–42. The AA genotype of the newly found 3′-UTR SNP +2852(A/G), was associated with a decreased risk of AD (pc = 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.

Keywords

Activity-regulated cytoskeleton-associated protein Single nucleotide polymorphism Gene association Alzheimer’s disease Memory Immediate-early gene 

References

  1. Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G (2010) Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci USA 107(5):2295–2300. doi:10.1073/pnas.0911829107 PubMedCrossRefGoogle Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265PubMedCrossRefGoogle Scholar
  3. Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26(3):231–245. doi:10.1007/BF02815140 PubMedCrossRefGoogle Scholar
  4. Blennow K, Ricksten A, Prince JA, Brookes AJ, Emahazion T, Wasslavik C, Bogdanovic N, Andreasen N, Batsman S, Marcusson J, Nagga K, Wallin A, Regland B, Olofsson H, Hesse C, Davidsson P, Minthon L, Jansson A, Palmqvist L, Rymo L (2000) No association between the alpha2-macroglobulin (A2 M) deletion and Alzheimer’s disease, and no change in A2 M mRNA, protein, or protein expression. J Neural Transm 107(8–9):1065–1079PubMedCrossRefGoogle Scholar
  5. Bramham CR, Worley PF, Moore MJ, Guzowski JF (2008) The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J Neurosci 28(46):11760–11767. doi:10.1523/jneurosci.3864-08.2008 PubMedCrossRefGoogle Scholar
  6. Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K (2010) The Arc of synaptic memory. Exp Brain Res 200(2):125–140 Epub 2009 Aug 2019PubMedCrossRefGoogle Scholar
  7. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8(1):79–84. doi:10.1038/nn1372 PubMedCrossRefGoogle Scholar
  8. Decker H, Jurgensen S, Adrover MF, Brito-Moreira J, Bomfim TR, Klein WL, Epstein AL, De Felice FG, Jerusalinsky D, Ferreira ST (2010) N-methyl-d-aspartate receptors are required for synaptic targeting of Alzheimer’s toxic amyloid-β peptide oligomers. J Neurochem 115(6):1520–1529. doi:10.1111/j.1471-4159.2010.07058.x PubMedCrossRefGoogle Scholar
  9. DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464. doi:10.1002/ana.410270502 PubMedCrossRefGoogle Scholar
  10. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29(13):4004–4015. doi:10.1523/jneurosci.5980-08.2009 PubMedCrossRefGoogle Scholar
  11. Dickey CA, Gordon MN, Mason JE, Wilson NJ, Diamond DM, Guzowski JF, Morgan D (2004) Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice. J Neurochem 88(2):434–442PubMedCrossRefGoogle Scholar
  12. Dynes JL, Steward O (2007) Dynamics of bidirectional transport of Arc mRNA in neuronal dendrites. J Comp Neurol 500(3):433–447. doi:10.1002/cne.21189 PubMedCrossRefGoogle Scholar
  13. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12(5):921–927PubMedGoogle Scholar
  14. Folstein MF, Folstein SE, McHugh PR (1975) “Mini–mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198. doi:0022-3956(75)90026-6 PubMedCrossRefGoogle Scholar
  15. Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K (2003) Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron 38(3):447–460PubMedCrossRefGoogle Scholar
  16. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296(5576):2225–2229PubMedCrossRefGoogle Scholar
  17. Giorgi C, Yeo GW, Stone ME, Katz DB, Burge C, Turrigiano G, Moore MJ (2007) The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 130(1):179–191. doi:10.1016/j.cell.2007.05.028 PubMedCrossRefGoogle Scholar
  18. Guzowski JF (2002) Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches. Hippocampus 12(1):86–104. doi:10.1002/hipo.10010 PubMedCrossRefGoogle Scholar
  19. Guzowski JF, McNaughton BL, Barnes CA, Worley PF (1999) Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat Neurosci 2(12):1120–1124. doi:10.1038/16046 PubMedCrossRefGoogle Scholar
  20. Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20(11):3993–4001PubMedGoogle Scholar
  21. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112. doi:10.1038/nrm2101 PubMedCrossRefGoogle Scholar
  22. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5(3):228–234. doi:10.1016/s1474-4422(06)70355-6 PubMedCrossRefGoogle Scholar
  23. Haug K, Kremerskothen J, Hallmann K, Sander T, Dullinger J, Rau B, Beyenburg S, Lentze MJ, Barnekow A, Elger CE, Propping P, Heils A (2000) Mutation screening of the chromosome 8q24.3-human activity-regulated cytoskeleton-associated gene (ARC) in idiopathic generalized epilepsy. Mol Cell Probes 14(4):255–260. doi:10.1006/mcpr.2000.0314 PubMedCrossRefGoogle Scholar
  24. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 103(13):5161–5166. doi:10.1073/pnas.0600948103 PubMedCrossRefGoogle Scholar
  25. Kobayashi H, Yamamoto S, Maruo T, Murakami F (2005) Identification of a cis-acting element required for dendritic targeting of activity-regulated cytoskeleton-associated protein mRNA. Eur J Neurosci 22(12):2977–2984PubMedCrossRefGoogle Scholar
  26. Kremerskothen J, Barnekow A (2000) Human activity-regulated cytoskeleton-associated gene (ARC) maps to chromosome 8q24. Chromosome Res 8(7):655PubMedCrossRefGoogle Scholar
  27. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24(45):10191–10200. doi:10.1523/jneurosci.3432-04.2004 PubMedCrossRefGoogle Scholar
  28. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27(4):796–807. doi:10.1523/jneurosci.3501-06.2007 PubMedCrossRefGoogle Scholar
  29. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95(11):6448–6453PubMedCrossRefGoogle Scholar
  30. Landgren S, Palmer MS, Skoog I, Minthon L, Wallin A, Andreasen N, Zetterberg M, Blennow K, Zetterberg H (2010) No association of VEGF polymorphims with Alzheimer’s disease. Neuromol Med 12(3):224–228 (Epub 2009 Oct 2020)CrossRefGoogle Scholar
  31. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357. doi:10.1038/nature04533 PubMedCrossRefGoogle Scholar
  32. Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U, Kuhl D (1995) Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci USA 92(12):5734–5738PubMedCrossRefGoogle Scholar
  33. Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14(5–6):143–149PubMedCrossRefGoogle Scholar
  34. Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14(2):433–445PubMedCrossRefGoogle Scholar
  35. Mattaliano MD, Montana ES, Parisky KM, Littleton JT, Griffith LC (2007) The Drosophila ARC homolog regulates behavioral responses to starvation. Mol Cell Neurosci 36(2):211–221. doi:10.1016/j.mcn.2007.06.008 PubMedCrossRefGoogle Scholar
  36. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34(7):939–944PubMedCrossRefGoogle Scholar
  37. Miyashita T, Kubik S, Lewandowski G, Guzowski JF (2008) Networks of neurons, networks of genes: an integrated view of memory consolidation. Neurobiol Learn Mem 89(3):269–284. doi:10.1016/j.nlm.2007.08.012 PubMedCrossRefGoogle Scholar
  38. Moga DE, Calhoun ME, Chowdhury A, Worley P, Morrison JH, Shapiro ML (2004) Activity-regulated cytoskeletal-associated protein is localized to recently activated excitatory synapses. Neuroscience 125(1):7–11PubMedCrossRefGoogle Scholar
  39. Palop JJ, Chin J, Bien-Ly N, Massaro C, Yeung BZ, Yu GQ, Mucke L (2005) Vulnerability of dentate granule cells to disruption of arc expression in human amyloid precursor protein transgenic mice. J Neurosci 25(42):9686–9693. doi:10.1523/jneurosci.2829-05.2005 PubMedCrossRefGoogle Scholar
  40. Panja D, Dagyte G, Bidinosti M, Wibrand K, Kristiansen AM, Sonenberg N, Bramham CR (2009) Novel translational control in Arc-dependent long term potentiation consolidation in vivo. J Biol Chem 284(46):31498–31511. doi:10.1074/jbc.M109.056077 PubMedCrossRefGoogle Scholar
  41. Peebles CL, Yoo J, Thwin MT, Palop JJ, Noebels JL, Finkbeiner S (2010) Arc regulates spine morphology and maintains network stability in vivo. Proc Natl Acad Sci USA 107(42):18173–18178. doi:10.1073/pnas.1006546107 PubMedCrossRefGoogle Scholar
  42. Perez-Cruz C, Nolte MW, van Gaalen MM, Rustay NR, Termont A, Tanghe A, Kirchhoff F, Ebert U (2011) Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer’s disease. J Neurosci 31(10):3926–3934PubMedCrossRefGoogle Scholar
  43. Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bosl, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52(3):437–444. doi:10.1016/j.neuron.2006.08.024 PubMedCrossRefGoogle Scholar
  44. Poling A, Morgan-Paisley K, Panos JJ, Kim EM, O’Hare E, Cleary JP, Lesne S, Ashe KH, Porritt M, Baker LE (2008) Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures. Behav Brain Res 193(2):230–234. doi:10.1016/j.bbr.2008.06.001 PubMedCrossRefGoogle Scholar
  45. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399(6738 Suppl):A23–A31PubMedGoogle Scholar
  46. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. doi:10.1126/science.1074069 PubMedCrossRefGoogle Scholar
  47. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842. doi:10.1038/nm1782 PubMedCrossRefGoogle Scholar
  48. Shepherd JD, Bear MF (2011) New views of Arc, a master regulator of synaptic plasticity. Nat Neurosci 14(3):279–284. doi:10.1038/nn.2708 PubMedCrossRefGoogle Scholar
  49. Steward O, Worley PF (2001) Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation. Neuron 30(1):227–240PubMedCrossRefGoogle Scholar
  50. Steward O, Wallace CS, Lyford GL, Worley PF (1998) Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites. Neuron 21(4):741–751PubMedCrossRefGoogle Scholar
  51. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580. doi:10.1002/ana.410300410 PubMedCrossRefGoogle Scholar
  52. Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ (2006) Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol 572(Pt 2):477–492. doi:10.1113/jphysiol.2005.103754 PubMedCrossRefGoogle Scholar
  53. Tzingounis AV, Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52(3):403–407. doi:10.1016/j.neuron.2006.10.016 PubMedCrossRefGoogle Scholar
  54. Vanderstichele H, Van Kerschaver E, Hesse C, Davidsson P, Buyse MA, Andreasen N, Minthon L, Wallin A, Blennow K, Vanmechelen E (2000) Standardization of measurement of beta-amyloid(1–42) in cerebrospinal fluid and plasma. Amyloid 7(4):245–258PubMedCrossRefGoogle Scholar
  55. Vanmechelen E, Vanderstichele H, Davidsson P, Van Kerschaver E, Van Der Perre B, Sjogren M, Andreasen N, Blennow K (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285(1):49–52. doi:S03043940(00)010363 PubMedCrossRefGoogle Scholar
  56. Vazdarjanova A, McNaughton BL, Barnes CA, Worley PF, Guzowski JF (2002) Experience-dependent coincident expression of the effector immediate-early genes arc and Homer 1a in hippocampal and neocortical neuronal networks. J Neurosci 22(23):10067–10071PubMedGoogle Scholar
  57. Viola KL, Velasco PT, Klein WL (2008) Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 12(1):51S–57SPubMedCrossRefGoogle Scholar
  58. von Otter M, Landgren S, Nilsson S, Lundvall C, Minthon L, Bogdanovic N, Andreasen N, Gustafson DR, Skoog I, Wallin A, Hakansson A, Nissbrandt H, Zetterberg M, Tasa G, Blennow K, Zetterberg H (2010a) Kinesin light chain 1 gene haplotypes in three conformational diseases. Neuromol Med 12(3):229–236 (Epub 2009 Nov 2013)CrossRefGoogle Scholar
  59. von Otter M, Landgren S, Nilsson S, Zetterberg M, Celojevic D, Bergstrom P, Minthon L, Bogdanovic N, Andreasen N, Gustafson DR, Skoog I, Wallin A, Tasa G, Blennow K, Nilsson M, Hammarsten O, Zetterberg H (2010b) Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer’s disease and age-related cataract. Mech Ageing Dev 131(2):105–110. doi:10.1016/j.mad.2009.12.007 CrossRefGoogle Scholar
  60. Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM (2008) Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59(1):84–97. doi:10.1016/j.neuron.2008.05.014 PubMedCrossRefGoogle Scholar
  61. Wegenast-Braun BM, Fulgencio Maisch A, Eicke D, Radde R, Herzig MC, Staufenbiel M, Jucker M, Calhoun ME (2009) Independent effects of intra- and extracellular Abeta on learning-related gene expression. Am J Pathol 175(1):271–282. doi:10.2353/ajpath.2009.090044 PubMedCrossRefGoogle Scholar
  62. Young KF, Pasternak SH, Rylett RJ (2009) Oligomeric aggregates of amyloid beta peptide 1–42 activate ERK/MAPK in SH-SY5Y cells via the alpha7 nicotinic receptor. Neurochem Int 55(8):796–801 (Epub 2009 Aug 2008)PubMedCrossRefGoogle Scholar
  63. Zetterberg M, Landgren S, Andersson ME, Palmer MS, Gustafson DR, Skoog I, Minthon L, Thelle DS, Wallin A, Bogdanovic N, Andreasen N, Blennow K, Zetterberg H (2008) Association of complement factor H Y402H gene polymorphism with Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 147B(6):720–726PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sara Landgren
    • 1
  • Malin von Otter
    • 2
  • Mona Seibt Palmér
    • 3
  • Caroline Zetterström
    • 2
  • Staffan Nilsson
    • 4
  • Ingmar Skoog
    • 2
  • Deborah R. Gustafson
    • 2
  • Lennart Minthon
    • 5
  • Anders Wallin
    • 2
  • Niels Andreasen
    • 6
  • Nenad Bogdanovic
    • 6
  • Jan Marcusson
    • 7
  • Kaj Blennow
    • 2
  • Henrik Zetterberg
    • 2
    • 8
  • Petronella Kettunen
    • 2
  1. 1.Department of Pharmacology, Institute of Neuroscience and PhysiologyThe Sahlgrenska Academy at the University of GothenburgGothenburgSweden
  2. 2.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and PhysiologyThe Sahlgrenska Academy at the University of GothenburgGothenburgSweden
  3. 3.Department of Clinical Chemistry and Transfusion Medicine, Institute of BiomedicineThe Sahlgrenska Academy at the University of GothenburgGothenburgSweden
  4. 4.Department of Mathematical Statistics, Institute of Mathematical SciencesChalmers University of TechnologyGothenburgSweden
  5. 5.Department of Clinical SciencesClinical Memory Research Unit, Lund UniversityMalmöSweden
  6. 6.Division of Clinical Geriatrics, Department of Neurobiology, Caring Science and SocietyKarolinska InstitutetStockholmSweden
  7. 7.Department of Clinical and Experimental Medicine, Division of Geriatric MedicineLinköping UniversityLinköpingSweden
  8. 8.UCL Institute of NeurologyLondonUK

Personalised recommendations