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Genetic and host factors for dementia in Down's syndrome

  • Nicole Schupf (a1)

The high risk for dementia in adults with Down's syndrome has been attributed to triplication and overexpression of the gene for amyloid precursor protein (APP). But the wide variation in age at onset must be due to other risk factors.


To identify factors which influence age at onset of dementia in Down's syndrome.


Studies of factors which influence formation of beta-amyloid (Aβ) were reviewed, including atypical karyotypes, susceptibility genotypes, gender and oestrogen deficiency, and individual differences in Aβ peptide levels.


The apolipoprotein E $4 allele, oestrogen deficiency and high levels of Aβl-42 peptide are associated with earlier onset of dementia, while atypical karyotypes and the apolipoprotein E $2 allele are associated with reduced mortality and reduced risk of dementia.


Factors which influence Aβ levels, rather than overexpression of APP, may account for the differences in age at onset of dementia in Down's syndrome.

Corresponding author
Nicole Schupf, Ph D, New York State Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY 10314. Tel: 001 718 494 5301; Fax: 001 718 494 5395; e-mail:
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Presented in part as the Blake Marsh Lecture at the Annual Meeting of the Royal College of Psychiatrists, 6 July 2000, Edinburgh.

Declaration of interest

Grants IIRG-90-067 and RG3-96-077 from the Alzheimer's Association, Federal grants AG14673, HD35897, P50AG08702 and funds from New York State through its Office of Mental Retardation and Developmental Disabilities.

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Aylward, E. H. Burt, D. B. Thorpe, L. U. et al (1997) Diagnosis of dementia in individuals with intellectual disability. Journal of Intellectual Disability Research, 41, 152164.
Bachman, D. L. Wolf, P. A. Linn, R. T. et al (1993) Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study. Neurology, 43, 515519.
Barrett-Conner, E. & Kritz-Silverstein, D. (1993) Estrogen replacement therapy and cognitive function in older women. Journal of the American Medical Association, 269, 26372641.
Benjamin, R. Leake, A. McArthur, F. K. et al (1994) Protective effect of apoE ∊2 in Alzheimer's disease. Lancet, 344, 473.
Borchelt, D. R. Thinakaran, G. Eckman, C. B. et al (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Abetal-42/1-40 ratio in vitro and in vivo. Neuron, 17, 10051013.
Brenner, D. E. Kukull, W. A. Stergachis, A. et al (1994) Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case–control study. American Journal of Epidemiology, 140, 262267.
Campbell, W. A. Lowther, J. McKenzie, I. et al (1982) Serum gonadotropins in Down syndrome. Journal of Medical Genetics, 19, 9899.
Chicoine, B. & McGuire, D. (1997) Longevity of a woman with Down syndrome: A case study. Mental Retardation, 35, 477479.
Corder, E. H. Saunders, A. M. Strittmatter, W. J. et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261, 921923.
Corder, E. H. Saunders, A. M. Risch, N. J. et al (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer's disease. Nature Genetics, 7, 180184.
Cosgrave, M.P. Tyrrell, J. Dreja, H. et al (1996) Lower frequency of apolipoprotein E4 allele in an ‘elderly’ Down's syndrome population. Biological Psychiatry, 40, 811813.
Cosgrave, M.P. Tyrrell, J. McCarron, M. et al (1999) Age at onset of dementia and age of menopause in women with Down's syndrome. Journal of Intellectual Disability Research, 43, 461465.
Cummings, B. & Cotman, C. (1995) Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet, 346, 15241528.
Deb, S. Braganza, J. & Norton, N. (2000) APOE ∊4 influences the manifestation of Alzheimer's disease in adults with Down's syndrome. British Journal of Psychiatry, 176, 468472.
Farrer, M. J. Crayton, L. Davies, G. E. et al (1997) Allelic variability in D21S11, but not in APP or APOE, is associated with cognitive decline in Down syndrome. Neuroreport, 8, 16451649.
Goate, A. Chartier-Harlin, M. C. Mullan, M. et al (1991) Segregation of a missense mutation of the amyloid precursor protein gene with familial Alzheimer's disease. Nature, 349, 704706.
Goodman, Y. Bruce, A. J. Cheng, B. et al (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. Journal of Neurochemistry, 66, 18361844.
Hardy, J. Crook, R. Perry, R. et al (1994) ApoE genotype and Down's syndrome. Lancet, 343, 979980.
Hasen, J. Boyar, R. M. & Shapiro, L. R. (1980) Gonadal function in trisomy 21. Hormone Research, 12, 345350.
Henderson, V. W. Paganini-Hill, A. Emmanuel, C. K. et al (1994) Estrogen replacement therapy in older women. Archives of Neurology, 51, 896900.
Henderson, V. W. Paganini-Hill, Miller, B. K. et al (2000) Estrogen for Alzheimer's disease in women: randomized, double-blind placebo-controlled trial. Neurology, 54, 295301.
Hestnes, A. Stovener, L. J. Husoy, O. et al (1991) Hormonal and biochemical disturbances in Down's syndrome. Journal of Mental Deficiency Research, 35, 179193.
Higuchi, S. Muramatsu, T. Matsushita, S. et al (1996) Presenilin-1 polymorphism and Alzheimer's disease. Lancet, 347, 1186.
Holland, A. J. Hon, J. Huppert, F. A. et al (1998) Population-based study of the prevalence and presentation of dementia in adults with Down's syndrome. British Journal of Psychiatry, 172, 493498.
Hsiang, Y-H. H. Berkovitz, G. D. Bland, G. L. et al (1987) Gonadal function in patients with Down syndrome. American Journal of Medical Genetics, 27, 449458.
Hyman, B. T. West, H. L. Rebeck, G.W. et al (1995) Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein Egenotype and trisomy 21 (Down syndrome). Proceedings of the National Academy of Science USA, 92, 35863590.
Iwatsubo, T. Odaka, A. Suzuki, N. et al (1994) Visualization of AB42(43) and AB40 in senile plaques with end-specific AB monoclonals: evidence that an initially deposited species is AB42(43). Neuron, 13, 4553.
Iwatsubo, T. Mann, D. M. Odaka, A. et al (1995) Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Annals of Neurology, 37, 294299.
Jaffe, A. Toran-Allerand, C. D. Greengard, P. et al (1994) Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. Journal of Biological Chemistry, 269, 1306513068.
Kehoe, P. Williams, J. Lovestone, S. et al (1996) Presenilin-1 polymorphism and Alzheimer's disease. The UK Alzheimer's Disease Collaborative Group. Lancet, 347, 1185.
Kosaka, T. Imagawa, M. Seki, K. et al (1997) The beta APP7I7 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at A beta 42(43). Neurology, 48, 741745.
Lai, F. & Williams, R. S. (1989) A prospective study of Alzheimer disease in Down syndrome. Archives of Neurology, 46, 849853.
Lai, F. Kamman, E. Rebeck, G.W. et al (1999) APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome. Neurology, 53, 331336.
Lambert, J. C. Perez-Tur, J. Dupire, M. J. et al (1996) Analysis of the APOE alleles' impact in Down's syndrome. Neuroscience Letters, 220, 5760.
Levy-Lehad, E. Wasco, W. Pookaj, P. et al (1995) Candidate gene for the chromosome I familial Alzheimer's disease locus. Science, 269, 973977.
Lippa, C. F. Smith, T. W. Saunders, A. M. et al (1997) Apolipoprotein E-2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology, 48, 515519.
Ma, J. Yee, A. Brewer, H. B. Jr et al (1994) Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature, 372, 9294.
Mann, D. M. (1988) Association between Alzheimer disease and Down syndrome. In Alzheimer Disease, Down Syndrome and their Relationship (eds Berg, J. Karlinsky, H. & Holland, A.), pp. 7192. Oxford: Oxford University Press.
Mann, D. M. Iwatsubo, T. Ihara, Y. et al (1996) Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. American Journal of Pathology, 148, 12571266.
Martins, R. N. Clarnette, R. Fisher, C. et al (1995) ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome. Neuroreport, 6, 15131516.
Mayeux, R. Stern, Y. Ottman, R. et al (1993) The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease. Annals of Neurology, 34, 752754.
Mayeux, R. Tang, M. X. Jacobs, D. M. et al (1999) Plasma amyloid beta-peptide 1–42 and incipient Alzheimer's disease. Annals of Neurology, 46, 412416.
McNamara, M. J. Gomez-Isla, T. & Hyman, B. T. (1998) Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease. Archives of Neurology, 55, 10011004.
Mehta, P. D. Dalton, A. J. Mehta, S. P. et al (1998) Increased plasma amyloid beta protein 1–42 levels in Down syndrome. Neuroscience Letters, 241, 1316.
Meyer, M. R. Tschantz, J. T. Norten, M. C. et al (1998) APOE genotype predicts when-not whether-one is predisposed to Alzheimer's disease. Nature Genetics, 19, 321322.
Mortel, K. F. & Meyer, J. S. (1995) Lack of postmenopausal estrogen therapy and risk of dementia. Journal of Neuropsychiatry and Clinical Neuroscience, 14, 332337.
Mulnard, R. A. Cotman, C. W. Kawas, C. W. (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. Journal of the American Medical Association, 283, 10071015.
Naslund, J. Haroutonian, V. Mohs, R. et al (2000) Correlation between elevated levels of amyloid B-peptide in the brain and cognitive decline. Journal of the American Medical Association, 283, 15711577.
Paganini-Hill, A. & Henderson, V. W. (1994) Estrogen deficiency and risk of Alzheimer's disease in women. American Journal of Epidemiology, 140, 256261.
Petanceska, S. S. Nagy, V. Frail, D. et al (2000) Ovariectomy and 17 beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Neurology, 27, 22122217.
Polvikoski, T. Sulkava, R. Haltia, M. et al (1995) Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. New England Journal of Medicine, 333, 12421247.
Prasher, V. P. & Krishnan, V. H. R. (1993) Age of onset and duration of dementiain people with Down syndrome: Integration of 98 reported cases in the literature. International Journal of Geriatric Psychiatry, 10, 2531.
Prasher, V. P. Chowdhury, T. A. Rowe, B. R. et al (1997) ApoE genotype and Alzheimer's disease in adults with Down syndrome: meta-analysis. American Journal of Mental Retardation, 102, 103110.
Prasher, V. P. Farrer, M. J. Kessling, A. M. et al (1998) Molecular mapping of Alzheimer-type dementia in Down's syndrome. Annals of Neurology, 43, 380383.
Raghavan, R. Khin-Nu, C. Brown, A. G. et al (1994) Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21). Neuroreport, 5, 13931396.
Roses, A. D. Strittmatter, W. J. Pericak-Vance, M. A. et al (1994) Clinical application of apolipoprotein E genotypingto Alzheimer'sdisease. Lancet, 343, 15641565.
Royston, M. Mann, D. Pickering-Brown, S. et al (1994) Apolipoprotein E epsilon 2 allele promotes longevity and protects patients with Down's syndrome from dementia. Neuroreport, 20, 25832585.
Rubinsztein, D. C. Hon, J. Stevens, F. et al (1999) ApoE genotypes and risk of dementia in Down syndrome. American Journal of Medical Genetics, 88, 344347.
Rumble, B. Retallack, R. Hillbach, C. et al (1989) Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. New England Journal of Medicine, 320, 14461452.
Saunders, A. M. Schmader, K. Breitner, J. C. et al (1993) Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet, 342, 710711.
Scheuner, D. Eckman, C. Jensen, M. et al (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine, 2, 864870.
Schupf, N. Kapell, D. Lee, J. H. et al (1996) Onset of dementia is associated with apolipoprotein E ∊4 in Down syndrome. Annals of Neurology, 40, 799801.
Schupf, N. Kapell, D. Nightingale, B. et al (1998) Earlier onset of Alzheimer's disease in men with Down syndrome. Neurology, 50, 991995.
Schupf, N. Patel, B. Silverman, W. et al (2001) Elevated plasma amyloid β-peptide 1–42 and onset of dementia in Down syndrome. Neuroscience Letters, 301, 199203.
Scott, W. K. Growden, J. H. Roses, A. D. et al (1996) Presenilin-1 polymorphism and Alzheimer's disease. Lancet, 347, 11861187.
Sekijima, Y. Ikeda, S. Tokuda, T. et al (1998) Prevalence of dementia of the Alzheimer type and apolipoprotein E phenotypes in aged patients with Down syndrome. European Neurology, 39, 234237.
Sherrington, R. Rogaev, E. I. Liang, Y. et al (1995) Cloning of a novel gene bearing missense mutations in early familial Alzheimer's disease. Nature, 375, 754760.
Tang, M. X. Jacobs, D. Stern, Y. et al (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet, 348, 429432.
Tokuda, T. Fukushima, T. Ikeda, S.-I. et al (1997) Plasma levels of amyloid β-proteins ABI-40 and ABI-42(43) are elevated in Down's syndrome. Annals of Neurology, 41, 271273.
Toran-Allerand, C. D. Miranda, R. C. Bentham, W. D. et al (1992) Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain. Proceedings of the National Academy of Science USA, 89, 46684672.
Tyrrell, J. Cosgrave, M. Hawi, Z. et al (1998) A protective effect of apolipoprotein E e2 allele on dementia in Down's syndrome. Biological Psychiatry, 43, 397400.
Tyrrell, J. Cosgrave, M. McPherson, J. et al (1999) Presenilin 1 and alpha-1-antichymotrypsin polymorphisms in Down syndrome: no effect on the presence of dementia. American Journal of Medical Genetics, 88, 616620.
van Gool, W. A. Evenhuis, H. M. & van Duijn, C. M. (1995) A case–control study of apolipoprotein E genotypes in Alzheimer's disease associated with Down's syndrome. Dutch Study Group on Down's Syndrome and Ageing. Annals of Neurology, 38, 225230.
Visser, F. E. Aldenkamp, A. P. van Huffelen, A. C. et al (1997) Prospective study of the prevalence of Alzheimer-type dementia in institutionalized individuals with Down syndrome. American Journal of Mental Retardation, 101, 400412.
Wisniewski, H. Wegiel, J. Popovitch, E. (1995) Age-associated development of diffuse and thioflavin-S-positive plaques in Down syndrome. Developmental Brain Dysfunction, 7, 330339.
Wisniewski, T. Morelli, L. Wegiel, J. et al (1995) The influence of apolipoprotein E isotypes on Alzheimer's disease pathology in 40 cases of Down's syndrome. Annals of Neurology, 37, 136138.
Wragg, M. Hutton, M. & Talbot, C. (1996) Genetic association between intronic polymorphism in presenilin-1 gene and late onset Alzheimer's disease. Lancet, 347, 509512.
Younkin, S. G. (1998) The role of A beta 42 in Alzheimer's disease. Journal of Physiology Paris, 92, 289292.
Zigman, W. Schupf, N. Haveman, M. et al (1997) The epidemiology of Alzheimer disease in intellectual disability: results and recommendations from an international conference. Journal of Intellectual Disability Research, 41 7680.
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Genetic and host factors for dementia in Down's syndrome

  • Nicole Schupf (a1)
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