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A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Abstract

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) — an Alzheimer disease risk factor — although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

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Figure 1: Development of pathology and dementia in AD-DS and Dup-APP.
Figure 2: Regions of chromosome 21 duplicated in Dup-APP EOAD and ICH.
Figure 3: Schematic of suggested mechanisms that are important in AD-DS and their related genes.

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References

  1. Lejeune, J., Gautier, M. & Turpin, R. Etude des chromosomes somatiques de neuf enfants mongoliens. C. R. Hebd. Seances Acad. Sci. 248, 1721–1722 (in French) (1959).

    CAS  PubMed  Google Scholar 

  2. de Graaf, G., Buckley, F. & Skotko, B. G. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am. J. Med. Genet. A 167A, 756–767 (2015).

    PubMed  Google Scholar 

  3. Wu, J. H. & Morris, J. K. Trends in maternal age distribution and the live birth prevalence of Down's syndrome in England and Wales: 1938–2010. Eur. J. Hum. Genet. 21, 943–947 (2013).

    PubMed  PubMed Central  Google Scholar 

  4. Wu, J. H. & Morris, J. K. The population prevalence of Down's syndrome in England and Wales in 2011. Eur. J. Hum. Genet. 21, 1016–1019 (2013).

    PubMed  PubMed Central  Google Scholar 

  5. Wiseman, F. K., Alford, K. A., Tybulewicz, V. L. J. & Fisher, E. M. C. Down syndrome — recent progress and future prospects. Hum. Mol. Genet. 18, R75–R83 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. McCarron, M., McCallion, P., Reilly, E. & Mulryan, N. A prospective 14-year longitudinal follow-up of dementia in persons with Down syndrome. J. Intellect. Disabil. Res. 58, 61–70 (2014).

    CAS  PubMed  Google Scholar 

  7. Zigman, W. B., Schupf, N., Urv, T., Zigman, A. & Silverman, W. Incidence and temporal patterns of adaptive behavior change in adults with mental retardation. Am. J. Mental Retard. 107, 161–174 (2002).

    Google Scholar 

  8. Hooli, B. V. et al. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology 78, 1250–1257 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kasuga, K. et al. Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J. Neurol. Neurosurg. Psychiatry 80, 1050–1052 (2009).

    CAS  PubMed  Google Scholar 

  10. McNaughton, D. et al. Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series. Neurobiol. Aging 33, 426.e13–426.e21 (2010).

    Google Scholar 

  11. Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 38, 24–26 (2006).

    CAS  PubMed  Google Scholar 

  12. Rovelet-Lecrux, A. et al. APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage. J. Neurol. Neurosurg. Psychiatry 78, 1158–1159 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sleegers, K. et al. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129, 2977–2983 (2006).

    PubMed  Google Scholar 

  14. Swaminathan, S. et al. Analysis of copy number variation in Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. PLoS ONE 7 e50640 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Thonberg, H. et al. Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient. BMC Res. Notes 4, 476 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Prasher, V. P. et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann. Neurol. 43, 380–383 (1998).

    CAS  PubMed  Google Scholar 

  17. Korbel, J. O. et al. The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc. Natl Acad. Sci. USA 106, 12031–12036 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Fraser, J. & Mitchell, A. Kalmuc idiocy: report of a case with autopsy with notes on 62 cases. J. Mental Sci. 22, 161–169 (1876).

    Google Scholar 

  19. Strydom, A. et al. Dementia in older adults with intellectual disabilities — epidemiology, presentation, and diagnosis. J. Intellect. Disabil. 7, 96–110 (2010).

    Google Scholar 

  20. Tyrrell, J. et al. Dementia in people with Down's syndrome. Int. J. Geriatr. Psychiatry 16, 1168–1174 (2001).

    CAS  PubMed  Google Scholar 

  21. Coppus, A. et al. Dementia and mortality in persons with Down's syndrome. J. Intellect. Disabil. Res. 50, 768–777 (2006).

    CAS  PubMed  Google Scholar 

  22. Visser, F. E., Aldenkamp, A. P., vanHuffelen, A. C., Kuilman, M. & Overweg, J. Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. Am. J. Mental Retard. 101, 400–412 (1997).

    CAS  Google Scholar 

  23. Krinsky-McHale, S. J. et al. Successful aging in a 70-year-old man with Down syndrome: a case study. Intellect. Dev. Disabil. 46, 215–228 (2008).

    PubMed  Google Scholar 

  24. Coppus, A. M. W. et al. Early age at menopause is associated with increased risk of Dementia and mortality in women with Down syndrome. J. Alzheimers Dis. 19, 545–550 (2010).

    PubMed  Google Scholar 

  25. Schupf, N. et al. Onset of dementia is associated with age at menopause in women with Down's syndrome. Ann. Neurol. 54, 433–438 (2003).

    PubMed  Google Scholar 

  26. Cosgrave, M. P., Tyrrell, J., McCarron, M., Gill, M. & Lawlor, B. A. Age at onset of dementia and age of menopause in women with Down's syndrome. J. Intellect. Disabil. Res. 43, 461–465 (1999).

    PubMed  Google Scholar 

  27. Draheim, C. C., Geijer, J. R. & Dengel, D. R. Comparison of intima-media thickness of the carotid artery and cardiovascular disease risk factors in adults with versus without the Down syndrome. Am. J. Cardiol. 106, 1512–1516 (2010).

    PubMed  Google Scholar 

  28. Zigman, W. B. et al. Cholesterol level, statin use and Alzheimer's disease in adults with Down syndrome. Neurosci. Lett. 416, 279–284 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ylaherttuala, S., Luoma, J., Nikkari, T. & Kivimaki, T. Downs-syndrome and atherosclerosis. Atherosclerosis 76, 269–272 (1989).

    CAS  Google Scholar 

  30. van de Louw, J., Vorstenbosch, R., Vinck, L., Penning, C. & Evenhuis, H. Prevalence of hypertension in adults with intellectual disability in the Netherlands. J. Intellect. Disabil. Res. 53, 78–84 (2009).

    CAS  PubMed  Google Scholar 

  31. Stampfer, M. J. Cardiovascular disease and Alzheimer's disease: common links. J. Internal Med. 260, 211–223 (2006).

    CAS  PubMed  Google Scholar 

  32. Stern, Y. Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol. 11, 1006–1012 (2012).

    PubMed  PubMed Central  Google Scholar 

  33. Zigman, W. B. et al. Alzheimer's disease in adults with Down syndrome. Int. Rev. Res. Ment. Retard. 36, 103–145 (2008).

    PubMed  PubMed Central  Google Scholar 

  34. Margallo-Lana, M. L. et al. Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology. J. Intellect. Disabil. Res. 51, 463–477 (2007).

    CAS  PubMed  Google Scholar 

  35. Devenny, D. A., Krinsky-McHale, S. J., Sersen, G. & Silverman, W. P. Sequence of cognitive decline in dementia in adults with Down's syndrome. J. Intellect. Disabil. Res. 44, 654–665 (2000).

    PubMed  Google Scholar 

  36. Devenny, D. A., Zimmerli, E. J., Kittler, P. & Krinsky-McHale, S. J. Cued recall in early-stage dementia in adults with Down's syndrome. J. Intellect. Disabil. Res. 46, 472–483 (2002).

    CAS  PubMed  Google Scholar 

  37. Krinsky-McHale, S. J., Devenny, D. A. & Silverman, W. P. Changes in explicit memory associated with early dementia in adults with Down's syndrome. J. Intellect. Disabil. Res. 46, 198–208 (2002).

    CAS  PubMed  Google Scholar 

  38. Adams, D. & Oliver, C. The relationship between acquired impairments of executive function and behaviour change in adults with Down syndrome. J. Intellect. Disabil. Res. 54, 393–405 (2010).

    CAS  PubMed  Google Scholar 

  39. Ball, S. L. et al. Personality and behaviour changes mark the early stages of Alzheimer's disease in adults with Down's syndrome: findings from a prospective population-based study. Int. J. Geriatr. Psychiatry 21, 661–673 (2006).

    PubMed  Google Scholar 

  40. Ball, S. L., Holland, A. J., Treppner, P., Watson, P. C. & Huppert, F. A. Executive dysfunction and its association with personality and behaviour changes in the development of Alzheimer's disease in adults with Down syndrome and mild to moderate learning disabilities. Br. J. Clin. Psychol. 47, 1–29 (2008).

    PubMed  Google Scholar 

  41. Holland, A. J., Hon, J., Huppert, F. A. & Stevens, F. Incidence and course of dementia in people with Down's syndrome: findings from a population-based study. J. Intellect. Disabil. Res. 44, 138–146 (2000).

    PubMed  Google Scholar 

  42. Oliver, C., Kalsy, S., McQuillan, S. & Hall, S. Behavioural excesses and deficits associated with dementia in adults who have Down syndrome. J. Appl. Res. Intellect. Disabil. 24, 208–216 (2011).

    Google Scholar 

  43. Nelson, L. D., Orme, D., Osann, K. & Lott, I. T. Neurological changes and emotional functioning in adults with Down Syndrome. J. Intellect. Disabil. Res. 45, 450–456 (2001).

    CAS  PubMed  Google Scholar 

  44. Powell, D. et al. Frontal white matter integrity in adults with Down syndrome with and without dementia. Neurobiol. Aging 35, 1562–1569 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. Jennings, D. et al. Age dependence of brain ß-amyloid deposition in Down syndrome: an [18F]florbetaben PET study. Neurology 84, 500–507 (2015).

    CAS  PubMed  Google Scholar 

  46. Masters, M. C., Morris, J. C. & Roe, C. M. 'Noncognitive' symptoms of early Alzheimer disease: a longitudinal analysis. Neurology 84, 617–622 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wallon, D. et al. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J. Alzheimers Dis. 30, 847–856 (2012).

    CAS  PubMed  Google Scholar 

  48. De Simone, R., Puig, X. S., Gélisse, P., Crespel, A. & Genton, P. Senile myoclonic epilepsy: delineation of a common condition associated with Alzheimer's disease in Down syndrome. Seizure 19, 383–389 (2010).

    PubMed  Google Scholar 

  49. Moller, J. C., Hamer, H. M., Oertel, W. H. & Rosenow, F. Late-onset myoclonic epilepsy in Down's syndrome (LOMEDS). Seizure 10, 303–305 (2001).

    CAS  PubMed  Google Scholar 

  50. d'Orsi, G. & Specchio, L. M. Progressive myoclonus epilepsy in Down syndrome patients with dementia. J. Neurol. 261, 1584–1597 (2014).

    CAS  PubMed  Google Scholar 

  51. Friedman, D., Honig, L. S. & Scarmeas, N. Seizures and epilepsy in Alzheimer's disease. CNS Neurosci. Ther. 18, 285–294 (2012).

    PubMed  Google Scholar 

  52. Vossel, K. A. et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 70, 1158–1166 (2013).

    PubMed  PubMed Central  Google Scholar 

  53. Irizarry, M. C. et al. Incidence of new-onset seizures in mild to moderate Alzheimer disease. Arch. Neurol. 69, 368–372 (2012).

    PubMed  PubMed Central  Google Scholar 

  54. Lott, I. T. et al. Down syndrome and dementia: seizures and cognitive decline. J. Alzheimers Dis. 29, 177–185 (2012).

    PubMed  PubMed Central  Google Scholar 

  55. Crayton, L., Oliver, C., Holland, A., Bradbury, J. & Hall, S. The neuropsychological assessment of age related cognitive deficits in adults with Down's syndrome. J. Appl. Res. Intellect. Disabil. 11, 255–272 (1998).

    Google Scholar 

  56. Dalton, A. J., Mehta, P. D., Fedor, B. L. & Patti, P. J. Cognitive changes in memory precede those in praxis in aging persons with Down syndrome. J. Intellect. Dev. Disabil. 24, 169–187 (1999).

    Google Scholar 

  57. Struwe, F. Histopathologische Untersuchungen über Entstehung und Wesen der senile Plaques. Z. Gesamte Neurol. Psy. 122, 291–307 (in German) (1929).

    Google Scholar 

  58. Glenner, G. G. & Wong, C. W. Alzheimer's disease and Downs syndrome — sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131–1135 (1984).

    CAS  PubMed  Google Scholar 

  59. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    CAS  PubMed  Google Scholar 

  60. Hardy, J. A. & Higgins, G. A. Alzheimer's disease — the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    CAS  PubMed  Google Scholar 

  61. Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments — abnormal phosphorylation of all 6 brain isoforms. Neuron 8, 159–168 (1992).

    CAS  PubMed  Google Scholar 

  62. Mann, D. M. A. Alzheimer's disease and Down's syndrome. Histopathology 13, 125–137 (1988).

    CAS  PubMed  Google Scholar 

  63. Wisniewski, H. M. & Rabe, A. Discrepancy between Alzheimer-type neuropathology and dementia in persons with Down's syndrome. Ann. NY Acad. Sci. 477, 247–260 (1986).

    CAS  PubMed  Google Scholar 

  64. Mann, D. M. A. The pathological association between Down syndrome and Alzheimer's disease. Mech. Ageing Dev. 43, 99–136 (1988).

    CAS  PubMed  Google Scholar 

  65. Leverenz, J. B. & Raskind, M. A. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp. Neurol. 150, 296–304 (1998).

    CAS  PubMed  Google Scholar 

  66. Braak, H. & Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  67. Egensperger, R. et al. Reverse relationship between β-amyloid precursor protein and beta-amyloid peptide plaques in Down's syndrome versus sporadic/familial Alzheimer's disease. Acta Neuropathol. 97, 113–118 (1999).

    CAS  PubMed  Google Scholar 

  68. Mann, D. M. A., Yates, P. O., Marcyniuk, B. & Ravindra, C. R. Loss of neurons from cortical and subcortical areas in Down's syndrome patients at middle-age — quantitative comparisons with younger Down's patients and patients with Alzheimer's disease. J. Neurol. Sci. 80, 79–89 (1987).

    CAS  PubMed  Google Scholar 

  69. Allsop, D., Kidd, M., Landon, M. & Tomlinson, A. Isolated senile plaque cores in Alzheimer's disease and Down's syndrome show differences in morphology. J. Neurol. Neurosurg. Psychiatry 49, 886–892 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Armstrong, R. A. Size frequency distributions of β-amyloid (4β) deposits: a comparative study of four neurodegenerative disorders. Folia Neuropathol. 50, 240–249 (2012).

    CAS  PubMed  Google Scholar 

  71. Bero, A. W. et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat. Neurosci. 14, 750–756 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gyure, K. A., Durham, R., Stewart, W. F., Smialek, J. E. & Troncoso, J. C. Intraneuronal Aβ-amyloid precedes development of amyloid plaques in Down syndrome. Arch. Pathol. Lab. Med. 125, 489–492 (2001).

    CAS  PubMed  Google Scholar 

  73. Hirayama, A., Horikoshi, Y., Maeda, M., Ito, M. & Takashima, S. Characteristic developmental expression of amyloid β40, 42 and 43 in patients with Down syndrome. Brain Dev. 25, 180–185 (2003).

    PubMed  Google Scholar 

  74. Iwatsubo, T., Mann, D. M. A., Odaka, A., Suzuki, N. & Ihara, Y. Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in Down syndrome. Ann. Neurol. 37, 294–299 (1995).

    CAS  PubMed  Google Scholar 

  75. Mori, C. et al. Intraneuronal Aβ42 accumulation in Down syndrome brain. Amyloid 9, 88–102 (2002).

    CAS  PubMed  Google Scholar 

  76. Wegiel, J. et al. Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration. Acta Neuropathol. 113, 389–402 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Wisniewski, K. E., Wisniewski, H. M. & Wen, G. Y. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann. Neurol. 17, 278–282 (1985).

    CAS  PubMed  Google Scholar 

  78. Wisniewski, K. E., Dalton, A. J., Mclachlan, D. R. C., Wen, G. Y. & Wisniewski, H. M. Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 35, 957–961 (1985).

    CAS  PubMed  Google Scholar 

  79. Burger, P. C. & Vogel, F. S. The development of pathologic changes of Alzheimer's disease and senile dementia in patients with Down's syndrome. Am. J. Pathol. 73, 457–476 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lemere, C. A. et al. Sequence of deposition of heterogeneous amyloid β-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3, 16–32 (1996).

    CAS  PubMed  Google Scholar 

  81. Ball, M. J. & Nuttall, K. Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer dementia. Ann. Neurol. 7, 462–465 (1980).

    CAS  PubMed  Google Scholar 

  82. Mann, D. M. A. & Esiri, M. M. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J. Neurol. Sci. 89, 169–179 (1989).

    CAS  PubMed  Google Scholar 

  83. Whalley, L. J. The dementia of Down's syndrome and its relevance to etiological studies of Alzheimer's disease. Ann. NY Acad. Sci. 396, 39–53 (1982).

    CAS  PubMed  Google Scholar 

  84. Ropper, A. H. & Williams, R. S. Relationship between plaques, tangles, and dementia in Down syndrome. Neurology 30, 639–644 (1980).

    CAS  PubMed  Google Scholar 

  85. Godridge, H., Reynolds, G. P., Czudek, C., Calcutt, N. A. & Benton, M. Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue. J. Neurol. Neurosurg. Psychiatry 50, 775–778 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Murphy, G. M. et al. Antigenic profile of plaques and neurofibrillary tangles in the amygdala in Down's syndrome: a comparison with Alzheimer's disease. Brain Res. 537, 102–108 (1990).

    CAS  PubMed  Google Scholar 

  87. Motte, J. & Williams, R. S. Age-related-changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain. Acta Neuropathol. 77, 535–546 (1989).

    CAS  PubMed  Google Scholar 

  88. Head, E. et al. Parallel compensatory and pathological events associated with Tau pathology in middle aged individuals with Down syndrome. J. Neuropathol. Exp. Neurol. 62, 917–926 (2003).

    CAS  PubMed  Google Scholar 

  89. Serrano-Pozo, A., Frosch, M. P., Masliah, E. & Hyman, B. T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1, a006189 (2011).

    PubMed  PubMed Central  Google Scholar 

  90. Mann, D. M. A. Cerebral amyloidosis, aging and Alzheimer's disease: a contribution from studies on Down's syndrome. Neurobiol. Aging 10, 397–399 (1989).

    CAS  PubMed  Google Scholar 

  91. Evenhuis, H. M. The natural history of dementia in Down's syndrome. Arch. Neurol. 47, 263–267 (1990).

    CAS  PubMed  Google Scholar 

  92. McCarron, M. O., Nicoll, J. A. R. & Graham, D. I. A quartet of Down's syndrome, Alzheimer's disease, cerebral amyloid angiopathy, and cerebral haemorrhage: interacting genetic risk factors. J. Neurol. Neurosurg. Psychiatry 65, 405–406 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Mendel, T., Bertrand, E., Szpak, G. M., Stepien, T. & Wierzba-Bobrowicz, T. Cerebral amyloid angiopathy as a cause of an extensive brain hemorrhage in adult patient with Down's syndrome — a case report. Folia Neuropathol. 48, 206–211 (2010).

    PubMed  Google Scholar 

  94. Naito, K. S., Sekijima, Y. & Ikeda, S. I. Cerebral amyloid angiopathy-related hemorrhage in a middle-aged patient with Down's syndrome. Amyloid 15, 275–277 (2008).

    CAS  PubMed  Google Scholar 

  95. Donahue, J. E., Khurana, J. S. & Adelman, L. S. Intracerebral hemorrhage in two patients with Down's syndrome and cerebral amyloid angiopathy. Acta Neuropathol. 95, 213–216 (1998).

    CAS  PubMed  Google Scholar 

  96. Handen, B. L. et al. Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. Alzheimers Dement. 8, 496–501 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Nelson, L. D. et al. Positron emission tomography of brain β-amyloid and Tau levels in adults with Down syndrome. Arch. Neurol. 68, 768–774 (2011).

    PubMed  PubMed Central  Google Scholar 

  98. Matveev, S. V. et al. A distinct subfraction of Aβ is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain. J. Neurochem. 131, 356–368 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hartley, S. L. et al. Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome. Brain 137, 2556–2563 (2014).

    PubMed  PubMed Central  Google Scholar 

  100. Landt, J. et al. Using positron emission tomography and carbon 11-labeled Pittsburgh compound B to image brain fibrillar β-amyloid in adults with Down syndrome safety, acceptability, and feasibility. Arch. Neurol. 68, 890–896 (2011).

    PubMed  Google Scholar 

  101. Lippa, C. F. et al. Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and Down syndrome. Arch. Neurol. 66, 1483–1488 (2009).

    PubMed  PubMed Central  Google Scholar 

  102. Davidson, Y. S. et al. TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol. 122, 703–713 (2011).

    PubMed  Google Scholar 

  103. Gibb, W. R. G., Mountjoy, C. Q., Mann, D. M. A. & Lees, A. J. A pathological study of the association between Lewy body disease and Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 52, 701–708 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Prasher, V. P., Airuehia, E. & Carey, M. The first confirmed case of Down syndrome with dementia with Lewy bodies. J. Appl. Res. Intellect. Disabil. 23, 296–300 (2010).

    Google Scholar 

  105. Cataldo, A. M. et al. Aβ localization in abnormal endosomes: association with earliest Aβ elevations in AD and Down syndrome. Neurobiol. Aging 25, 1263–1272 (2004).

    CAS  PubMed  Google Scholar 

  106. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452–1458 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Hooli, B. V. et al. Rare autosomal copy number variations in early-onset familial Alzheimer's disease. Mol. Psychiatry 19, 676–681 (2014).

    CAS  PubMed  Google Scholar 

  108. Llado, A. et al. Large APP locus duplication in a sporadic case of cerebral haemorrhage. Neurogenetics 15, 145–149 (2014).

    PubMed  Google Scholar 

  109. Cabrejo, L. et al. Phenotype associated with APP duplication in five families. Brain 129, 2966–2976 (2006).

    PubMed  Google Scholar 

  110. Noebels, J. A perfect storm: converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation. Epilepsia 52, 39–46 (2011).

    PubMed  PubMed Central  Google Scholar 

  111. Griffiths-Jones, S. The microRNA registry. Nucleic Acids Res. 32, D109–D111 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Vilardell, M. et al. Meta-analysis of heterogeneous Down syndrome data reveals consistent genome-wide dosage effects related to neurological processes. BMC Genomics 12, 229 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. Letourneau, A. et al. Domains of genome-wide gene expression dysregulation in Down's syndrome. Nature 508, 345–350 (2014).

    CAS  PubMed  Google Scholar 

  114. Horvath, S. et al. Accelerated epigenetic aging in Down syndrome. Aging Cell 14, 491–495 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Cheon, M. S., Dierssen, M., Kim, S. H. & Lubec, G. Protein expression of BACE1, BACE2 and APP in Down syndrome brains. Amino Acids 35, 339–343 (2008).

    CAS  PubMed  Google Scholar 

  116. Choi, J. H. K. et al. Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model. J. Neurochem. 110, 1818–1827 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Seo, H. & Isacson, O. Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice. Exp. Neurol. 193, 469–480 (2005).

    CAS  PubMed  Google Scholar 

  118. Teller, J. K. et al. Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down's syndrome. Nat. Med. 2, 93–95 (1996).

    CAS  PubMed  Google Scholar 

  119. Busciglio, J. et al. Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 33, 677–688 (2002).

    CAS  PubMed  Google Scholar 

  120. Govoni, S. et al. Fibroblasts of patients affected by Down's syndrome oversecrete amyloid precursor protein and are hyporesponsive to protein kinase C stimulation. Neurology 47, 1069–1075 (1996).

    CAS  PubMed  Google Scholar 

  121. Murray, A., Letourneau, A. & Canzonetta, C. Isogenic induced pluripotent stem cell lines from an adult with mosaic Down syndrome model accelerated neuronal ageing and neurodegeneration. Stem Cells 33, 2077–2084 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Shi, Y. C. et al. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci. Transl. Med. 4, 124ra29 (2012).

    PubMed  PubMed Central  Google Scholar 

  123. Wolvetang, E. W. et al. The chromosome 21 transcription factor ETS2 transactivates the β-APP promoter: implications for Down syndrome. Biochim. Biophys. Acta 1628, 105–110 (2003).

    CAS  PubMed  Google Scholar 

  124. Dorval, V., Mazzella, M. J., Mathews, P. M., Hay, R. T. & Fraser, P. E. Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins. Biochem. J. 404, 309–316 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Li, Y. H. et al. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc. Natl Acad. Sci. USA 100, 259–264 (2003).

    CAS  PubMed  Google Scholar 

  126. Ryoo, S. R. et al. Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease. J. Neurochem. 104, 1333–1344 (2008).

    CAS  PubMed  Google Scholar 

  127. Wang, X. et al. Sorting nexin 27 regulates Aβ production through modulating γ-secretase activity. Cell Rep. 9, 1023–1033 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Mok, K. Y. et al. Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome. Neurobiol. Aging 35, 1513.e1–1513.e5 (2014).

    CAS  Google Scholar 

  129. Sun, X. L., He, G. Q. & Song, W. H. BACE2, as a novel APP θ-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. FASEB J. 20, 1369–1376 (2006).

    CAS  PubMed  Google Scholar 

  130. Azkona, G., Levannon, D., Groner, Y. & Dierssen, M. In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model. Amino Acids 39, 1571–1580 (2010).

    CAS  PubMed  Google Scholar 

  131. Holler, C. J. et al. BACE2 expression increases in human neurodegenerative disease. Am. J. Pathol. 180, 337–350 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Patel, A. et al. Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome. Neurosci. Lett. 487, 144–148 (2011).

    CAS  PubMed  Google Scholar 

  133. Prasher, V. P. et al. Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome. Int. J. Geriatr. Psychiatry 23, 1134–1140 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Deb, S. et al. APOE epsilon 4 influences the manifestation of Alzheimer's disease in adults with Down's syndrome. Br. J. Psychiatry 176, 468–472 (2000).

    CAS  PubMed  Google Scholar 

  135. Coppus, A. M. W. et al. The impact of apolipoprotein E on dementia in persons with Down's syndrome. Neurobiol. Aging 29, 828–835 (2008).

    CAS  PubMed  Google Scholar 

  136. Schupf, N. et al. Onset of dementia is associated with apolipoprotein E epsilon 4 in Down's syndrome. Ann. Neurol. 40, 799–801 (1996).

    CAS  PubMed  Google Scholar 

  137. Hyman, B. T. et al. Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc. Natl Acad. Sci. USA 92, 3586–3590 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Royston, M. C. et al. Apolipoprotein-e epsilon-2 allele promotes longevity and protects patients with Down's syndrome from dementia. Neuroreport 5, 2583–2585 (1994).

    CAS  PubMed  Google Scholar 

  139. Jones, E. L. et al. Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome. Neurobiol. Aging 34, 2441.e1–2441.e5 (2013).

    CAS  Google Scholar 

  140. Lee, J. H. et al. Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome. Neurosci. Lett. 425, 105–109 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Salehi, A. et al. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51, 29–42 (2006).

    CAS  PubMed  Google Scholar 

  142. Torroja, L., Chu, H., Kotovsky, I. & White, K. Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9, 489–492 (1999).

    CAS  PubMed  Google Scholar 

  143. Jiang, Y. et al. Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition. Proc. Natl Acad. Sci. USA 107, 1630–1635 (2010).

    CAS  PubMed  Google Scholar 

  144. Barbosa, S., Pratte, D., Schwarz, H., Pipkorn, R. & Singer-Kruger, B. Oligomeric Dop1p is part of the endosomal Neo1p–Ysl2p–Arl1p membrane remodeling complex. Traffic 11, 1092–1106 (2010).

    CAS  PubMed  Google Scholar 

  145. Swaminathan, S. et al. Analysis of copy number variation in Alzheimer's disease: the NIA-LOAD/NCRAD family study. Curr. Alzheimer Res. 9, 801–814 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Chapman, J. et al. A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk. Hum. Mol. Genet. 22, 816–824 (2013).

    CAS  PubMed  Google Scholar 

  147. Yang, D. S. et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain 134, 258–277 (2011).

    PubMed  Google Scholar 

  148. Cossec, J. C. et al. Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. Hum. Mol. Genet. 21, 3156–3172 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. McIntire, L. B. J. et al. Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J. Neurosci. 32, 15271–15276 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhu, L. et al. Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model. J. Biol. Chem. 288, 32050–32063 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Busciglio, J. & Yankner, B. A. Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro. Nature 378, 776–779 (1995).

    CAS  PubMed  Google Scholar 

  152. Shukkur, E. A. et al. Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome. Hum. Mol. Genet. 15, 2752–2762 (2006).

    CAS  PubMed  Google Scholar 

  153. Phillips, A. C. et al. Defective mitochondrial function in vivo in skeletal muscle in adults with Down's syndrome: a 31P-MRS study. PLoS ONE 8, e84031 (2013).

    PubMed  PubMed Central  Google Scholar 

  154. Weick, J. P. et al. Deficits in human trisomy 21 iPSCs and neurons. Proc. Natl Acad. Sci. USA 110, 9962–9967 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Zigman, W. B. Atypical aging in Down syndrome. Dev. Disabil. Res. Rev. 18, 51–67 (2013).

    PubMed  Google Scholar 

  156. Picard, M. & Mcewen, B. S. Mitochondria impact brain function and cognition. Proc. Natl Acad. Sci. USA 111, 7–8 (2014).

    CAS  PubMed  Google Scholar 

  157. Lott, I. T. et al. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am. J. Med. Genet. A 155A, 1939–1948 (2011).

    PubMed  PubMed Central  Google Scholar 

  158. Carlson, G. A. et al. Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum. Mol. Genet. 6, 1951–1959 (1997).

    CAS  PubMed  Google Scholar 

  159. Murakami, K. et al. SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease. J. Biol. Chem. 286, 44557–44568 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Zis, P., Dickinson, M., Shende, S., Walker, Z. & Strydom, A. Oxidative stress and memory decline in adults with Down syndrome: longitudinal study. J. Alzheimers Dis. 31, 277–283 (2012).

    CAS  PubMed  Google Scholar 

  161. deHaan, J. B. et al. Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum. Mol. Genet. 5, 283–292 (1996).

    CAS  Google Scholar 

  162. Anderson, J. S. et al. Abnormal brain synchrony in Down syndrome. Neuroimage Clin. 2, 703–715 (2013).

    PubMed  PubMed Central  Google Scholar 

  163. Belichenko, P. V. et al. Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome. J. Comp. Neurol. 512, 453–466 (2008).

    Google Scholar 

  164. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007).

    CAS  PubMed  Google Scholar 

  165. Schmidt-Sidor, B., Wisniewski, K. E., Shepard, T. H. & Sersen, E. A. Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months. Clin. Neuropathol. 9, 181–190 (1990).

    CAS  PubMed  Google Scholar 

  166. Takashima, S., Becker, L. E., Armstrong, D. L. & Chan, F. Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study. Brain Res. 225, 1–21 (1981).

    CAS  PubMed  Google Scholar 

  167. Adorno, M. et al. Usp16 contributes to somatic stem-cell defects in Down's syndrome. Nature 501, 380–384 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Canzonetta, C. et al. DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am. J. Hum. Genet. 83, 388–400 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hibaoui, Y. et al. Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. EMBO Mol. Med. 6, 259–277 (2014).

    CAS  PubMed  Google Scholar 

  170. Chang, K. T. & Min, K. T. Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: implications for Down syndrome. Proc. Natl Acad. Sci. USA 106, 17117–17122 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Cvetkovska, V., Hibbert, A. D., Emran, F. & Chen, B. E. Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting. Nat. Neurosci. 16, 677–682 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Wang, B. P. et al. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons. J. Neurosci. 34, 13314–13325 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Nicolas, M. & Hassan, B. A. Amyloid precursor protein and neural development. Development 141, 2543–2548 (2014).

    CAS  PubMed  Google Scholar 

  174. Ma'ayan, A., Gardiner, K. J. & Iyengar, R. The cognitive phenotype of Down syndrome: insights from intracellular network analysis. NeuroRx 3, 396–406 (2006).

    PubMed  PubMed Central  Google Scholar 

  175. Drewes, G. et al. Dephosphorylation of Tau-protein and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. Febs Lett. 336, 425–432 (1993).

    CAS  PubMed  Google Scholar 

  176. Liu, F. et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Woods, Y. L. et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Dowjat, W. K. et al. Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci. Lett. 413, 77–81 (2007).

    CAS  PubMed  Google Scholar 

  179. Shi, J. et al. Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of Tau in Down syndrome. J. Biol. Chem. 283, 28660–28669 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Wegiel, J. et al. Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat Tau protein in Down syndrome. J. Neuropathol. Exp. Neurol. 70, 36–50 (2011).

    CAS  PubMed  Google Scholar 

  181. Moore, S. et al. APP metabolism regulates Tau protestasis in human cerebral cortex neurons. Cell Rep. 11, 689–696 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Lu, T. et al. REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448–454 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Kimura, R. et al. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between β-amyloid production and tau phosphorylation in Alzheimer disease. Hum. Mol. Genet. 16, 15–23 (2007).

    CAS  PubMed  Google Scholar 

  184. Vazquez-Higuera, J. L. et al. DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort. BMC Med. Genet. 10, 129 (2009).

    PubMed  PubMed Central  Google Scholar 

  185. Cooper, S. A. et al. Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial. Trials 15, 202 (2014).

    PubMed  PubMed Central  Google Scholar 

  186. Phillips, M. C. Molecular mechanisms of cellular cholesterol efflux. J. Biol. Chem. 289, 24020–24029 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Kim, W. S. et al. Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-β peptide generation. J. Biol. Chem. 282, 2851–2861 (2007).

    CAS  PubMed  Google Scholar 

  188. Tansley, G. H. et al. The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of β-amyloid precursor protein. J. Lipid Res. 48, 1022–1034 (2007).

    CAS  PubMed  Google Scholar 

  189. Burgess, B. L. et al. ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo. J. Lipid Res. 49, 1254–1267 (2008).

    CAS  PubMed  Google Scholar 

  190. Perry, V. H. & Holmes, C. Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10, 217–224 (2014).

    CAS  PubMed  Google Scholar 

  191. Wilcock, D. M. & Griffin, W. S. T. Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J. Neuroinflammation 10, 84 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Griffin, W. S. T. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Naude, P. J. W. et al. Serum NGAL is associated with distinct plasma amyloid-β peptides according to the clinical diagnosis of dementia in Down syndrome. J. Alzheimers Dis. 45, 733–743 (2015).

    CAS  PubMed  Google Scholar 

  194. Mann, D. M. A. et al. Microglial cells and amyloid-β protein (A) deposition — association with Aβ40-containing plaques. Acta Neuropathol. 90, 472–477 (1995).

    CAS  PubMed  Google Scholar 

  195. Xue, Q. S. & Streit, W. J. Microglial pathology in Down syndrome. Acta Neuropathol. 122, 455–466 (2011).

    CAS  PubMed  Google Scholar 

  196. Sheng, J. G., Mrak, R. E. & Griffin, W. S. T. S100β protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaques. J. Neurosci. Res. 39, 398–404 (1994).

    CAS  PubMed  Google Scholar 

  197. Mori, T. et al. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. Glia 58, 300–314 (2010).

    PubMed  PubMed Central  Google Scholar 

  198. Esposito, G. et al. S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells. J. Cell. Mol. Med. 12, 914–927 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Chen, C. et al. Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat. Commun. 5, 4430 (2014).

    CAS  PubMed  Google Scholar 

  200. Mills, S. M. et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev. Neurol. 169, 737–743 (2013).

    CAS  PubMed  Google Scholar 

  201. Bothwell, M. & Giniger, E. Alzheimer's disease: neurodevelopment converges with neurodegeneration. Cell 102, 271–273 (2000).

    CAS  PubMed  Google Scholar 

  202. Purro, S. A., Galli, S. & Salinas, P. C. Dysfunction of Wnt signaling and synaptic disassembly in neurodegenerative diseases. J. Mol. Cell Biol. 6, 75–80 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Karmiloff-Smith, A. et al. Genetic and environmental vulnerabilities in children with neurodevelopmental disorders. Proc. Natl Acad. Sci. USA 109, 17261–17265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Moran, P. M., Higgins, L. S., Cordell, B. & Moser, P. C. Age-related learning-deficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein. Proc. Natl Acad. Sci. USA 92, 5341–5345 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Yamaguchi, F. et al. Transgenic mice for the amyloid precursor protein 695 isoform have impaired spatial memory. Neuroreport 2, 781–784 (1991).

    CAS  PubMed  Google Scholar 

  206. Mucke, L. et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Balducci, C. & Forloni, G. A.P. P. Transgenic mice: their use and limitations. Neuromolecular Med. 13, 117–137 (2011).

    CAS  PubMed  Google Scholar 

  208. Brault, V., Pereira, P., Duchon, A. & Herault, Y. Modeling chromosomes in mouse to explore the function of genes, genomic disorders, and chromosomal organization. PLoS Genet. 2, e86 (2006).

    PubMed  PubMed Central  Google Scholar 

  209. Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Li, L. B. et al. Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell 11, 615–619 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Jiang, J. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Chang, C. Y. et al. N-butylidenephthalide attenuates Alzheimer's disease-like cytopathy in Down syndrome induced pluripotent stem cell-derived neurons. Sci. Rep. 5, 8744 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are funded by a Wellcome Trust Strategic Award (grant number: 098330/Z/12/Z) awarded to The London Down Syndrome (LonDownS) Consortium (J.H., A.K-S., D.N., V.L.J.T. E.M.C.F. and A.S.) and the Medical Research Council (programme number U117527252; awarded to V.L.J.T.), as well as by awards from Alzheimer Research UK (awarded to F.K.W and E.M.C.F), Alzheimer Society (awarded to E.M.C.F and F.K.W.), Bailey Thomas Trust (awarded to A.S.), Epilepsy Research UK (awarded to F.K.W.), Lee Kong Chian School of Medicine, Nanyang Technological University Start-up Grant, and Singapore Ministry of Education Academic Research Fund Tier 1(2014-T1-001-173; awarded to D.N).

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Correspondence to Elizabeth M. C. Fisher.

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Competing interests

A.S. has participated in clinical trials sponsored by F. Hoffmann-La Roche of medication to ameliorate some of the co-morbidities associated with fragile X syndrome and Down syndrome. He has acted as an adviser to the UK Down Syndrome Association and is an advisory board member of the LuMind Foundation (USA). F.K.W., T.A.-J., J.H., A.K.-S., D.N., V.L.J.T. and E.M.C.F. declare no competing interests.

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Prevalence and incidence studies of AD-DS since 19951-11 (PDF 143 kb)

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AD-DS neuropathological studies1-17 (PDF 167 kb)

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DupAPP clinical and pathological summary1-11 (PDF 133 kb)

Glossary

Dyspraxia

Disrupted fine or gross motor coordination.

Early-onset Alzheimer disease

(EOAD). Occurrence of Alzheimer disease before the age of 65 years.

Euploid

Having a normal chromosome number (46 chromosomes in 23 pairs in humans).

Executive functioning

Mental processing skills involving the frontal cortex; used for planning, attention focusing, working memory, mental flexibility and self-control.

Incidence

The rate of new occurrences of a disorder within a specified period of time.

Lewy bodies

Protein aggregates typically containing α-synuclein.

Myoclonic jerks

Brief involuntary muscle twitches that are a medical sign of various neurological disorders.

Parkinsonism

A clinical syndrome including bradykinesia (slow movements), muscle rigidity and tremor, often due to the neurodegenerative condition Parkinson disease but also associated with other neurological conditions, toxins and medications.

Prevalence

The number of cases of a disorder at one time within a population.

Tonic–clonic seizures

A common type of epileptic seizure with a tonic phase (stiffening of muscles and loss of consciousness) followed by a clonic phase (rapid, rhythmic jerking of arms and legs).

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Wiseman, F., Al-Janabi, T., Hardy, J. et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16, 564–574 (2015). https://doi.org/10.1038/nrn3983

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