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The Genetics of Alzheimer’s Disease and the Ethical Implications for Prevention

  • P. McGuffin
  • M. Sargeant
  • G. Weppner

Abstract

Senile dementia of the Alzheimer type is probably the commonest form of dementing illness after the age of 65 years in most western populations. The classical presenile form of Alzheimer’s disease is considerably less common but it is again among the most frequent causes of cognitive decline in late middle age. Since the presenile and senile forms show the same characteristic histopathology, they are now both often referred to simply as Alzheimer’s disease’ (AD). Both types tend to show familial aggregation and this seems to be particularly marked in early onset cases. Despite the consistency of reports of familiality and despite recent improvements in the understanding of the neuropathology and neurochemistry of AD, the precise aetiology remains a puzzle. This would doubtless be a disappointment to Alzheimer, who described AD and its typical neuropathological lesions in 1907, not long after his head of department, Kraepelin (1922), had effected his famous separation of the psychoses of adult life into dementia praecox and manic depressive insanity. Both men believed that they had classified conditions with a constitutional basis but only Alzheimer had clear neuropathological evidence on his side. More than 80 years on, the three conditions continue to present major challenges for genetic research and for therapeutic endeavour but, if anything, AD is the most aetiologically enigmatic and the most difficult to treat.

Keywords

Genetic Counselling Alzheimer Type Senile Dementia Predictive Testing Paired Helical Filament 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Breitner JCS, Folstein MF, Murphy EA (1986) Familial aggregation in Alzheimer dementia. I. A Model for the age-dependent expression of an autosomal dominant gene. J Psychiatr Res 20: 31–43PubMedCrossRefGoogle Scholar
  2. Davies K, Read AP (1988) Molecular basis of inherited disease. IRL, OxfordGoogle Scholar
  3. Delabar J-M, Goldgaber D, Lamour Y. Nicole A, Huret J-L, Degrouchy J, Brown P, Gajdusek DC, Sinet P-M (1987) Beta-amyloid gene duplicating in Alzheimer’s disease and karyotypically normal Down’s syndrome. Science 235: 1390–1392PubMedCrossRefGoogle Scholar
  4. Donis-Keller H, Green P, Helms C, Cartinhour S, Weifenbach B, Stephens K, Keith TP, Bowden DW, et al. (1987) A genetic linkage map of the human genome. Cell 51: 634–641Google Scholar
  5. Edwards JH (1960) The simulation of Mendelism. Acta Genet 10: 63–70PubMedGoogle Scholar
  6. Elandt-Johnson RC (1971) Probability models and statistical methods in genetics. Wiley, New YorkGoogle Scholar
  7. Elston RL, Stewart J (1971) A general model for genetic analysis of pedigree data. Hum Hered 21: 523–542PubMedCrossRefGoogle Scholar
  8. Fahy, F (1989) Different options for prenatal testing for Huntington’s disease using DAN probes. J Med Genet 26: 353–603PubMedCrossRefGoogle Scholar
  9. Foncin JF, Salmon D, Bruni AC (1986) Genetics of Alzheimer’s disease: a large kindred with apparent Mendelian transmission; possible implications for a linkage study. In: Briley M, Kato A, Weber M (eds) New concepts in Alzheimer’s disease, Macmillan, London, pp 242–256Google Scholar
  10. Gardiner K, Watkins PC, Munke M, Drabkin HA, Jones C, Patterson D (1988) A partial physical map of human chromosome 21. Somatic Cell Mol Genet 14: 633–638CrossRefGoogle Scholar
  11. Goate AM, Hardy JA, Owen MJ (1989) The genetic aetiology of Alzheimer’s disease. Int Rev Psychiatry 1: 243–248CrossRefGoogle Scholar
  12. Goldgaber D, Lerman ML, McBride OW, Sffiotti U, Gajdusek DC (1987) Characterisation and chromosomal localisation of cDNA encoding brain amyloid of Alzheimer’s disease. Science 235: 877–880PubMedCrossRefGoogle Scholar
  13. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson A, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, Young AB, Shoulson I, Bonilla E, Martin JB (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306: 234–238PubMedCrossRefGoogle Scholar
  14. Hardy JA, Goate AM, Owen MJ, Mullian MJ, Rossor MN, Pearson RCA (1989) Modelling the occurrence of pathology of Alzheimer’s disease. Neurobiol Aging 10: 429–431PubMedCrossRefGoogle Scholar
  15. Harper PS (1988) Practical genetic counselling, 3rd edn Wright, LondonGoogle Scholar
  16. Harper PS, Morris MJ (1990) Genetic testing for Huntington’s disease. (Editorial). Br Med J 300: 1089–1090CrossRefGoogle Scholar
  17. Heston LL, Mastri AR (1977) The genetics of Alzheimer’s disease. Associations with haemotologic malignancy and Down’s syndrome. Arch Gen Psychiatry 34: 396–406Google Scholar
  18. Heyman A, Wilkinson WE, Stafford JA, Heims MJ, Sigmon AH, Weinberge T (1984) Alzheimer’s disease. A study of epidemiological aspects. Ann Neurol 15: 335–341PubMedCrossRefGoogle Scholar
  19. Hodge SE, Spence MA (1982) Some epistatic two locus models of disease II. The confounding of linkage and association. Am J Hum Genet 33: 396–406Google Scholar
  20. Jarvik LF, Ruth V, Matsuyama SS (1980) Organic brain syndrome and aging: a six year follow-up of surviving twins. Arch Gen Psychiatry 37: 280–286PubMedGoogle Scholar
  21. Kallmann FJ (1956) Genetic aspects of mental disorders in later life. In: Kaplan OJ (ed) disorders in later life, 2nd edn. Oxford University Press, London, pp 24–46Google Scholar
  22. Kraepelin E (1922) Manic depressive insanity and paranoia. Livingstone, EdinburghGoogle Scholar
  23. Lalouel DM, Rao DC, Morton ME, Elston RC (1983) A unified model for complex segregation analysis. Am J Hum Genet 35: 816–826PubMedGoogle Scholar
  24. Larsson T, Sjogren T, Jacobson G (1963) Senile dementia: a clinical, sociomedical and genetic study. Acta Psychiatr Scand [Suppl 167] 39: 1–259Google Scholar
  25. Levy R (1990) Controversies in therapeutics: are drugs targetted at Alzheimer’s disease useful? Useful for what? Br Med J 300: 1131–1132CrossRefGoogle Scholar
  26. Martin RL, Gerteis G, Gabrielli WF, Martin WF (1988) A family-genetic study of dementia of Alzheimer type. Arch Gen Psychiatry 45: 894–900PubMedGoogle Scholar
  27. McGuffin P, Sargeant M (1989) Ethics and psychaitric genetics. Curr Sci 2: 681–684Google Scholar
  28. Meyer JE (1988) The fate of the mentally ill in Germany during the Third Reich. Psychol Med 18: 575–581PubMedCrossRefGoogle Scholar
  29. Morris MJ, Tyler A, Harper PS (1988) Adoption and genetic prediction for Huntington’s disease. Lancet 2: 1069PubMedCrossRefGoogle Scholar
  30. Morris MJ, Tyler A, Lazarou L, Meredith L, Harper PS (1989) Problems in genetic prediction of Huntington’s disease. Lancet 1: 601–603CrossRefGoogle Scholar
  31. Morton NE, Maclean CJ (1974) Analysis of familial resemblance. III. Complex segregation analysis of quantitative traits. Am J Hum Genet 26: 489–503PubMedGoogle Scholar
  32. Murphy EA, Chase GA (1975) Principles of genetic counselling. Year Book Medical Publishers, ChicagoGoogle Scholar
  33. Nee LE, Polinski RJ, Eldridge R, Weingartner H, Smallberg S, Ebert M (1983) A family with histologically confirmed Alzheimer’s disease. Arch Neurol 40: 203–208PubMedGoogle Scholar
  34. Nee LE, Eldridge R, Sunderland T et al. (1987) Dementia of the Alzheimer type: clinical and family study of 22 twin pairs. Neurology 37: 359–363PubMedGoogle Scholar
  35. Owen MJ, James LA, Hardy JA, Williamson R, Goate AM (1990) Physical mapping around the Alzheimer disease locus on the proximal long arm of chromosome 21. Am J Hum Genet 46: 316–322PubMedGoogle Scholar
  36. Pericak-Vance MA, Yamaoka LH, Haynes CS, Speer MC, Haines JL, Gaskell PC, Hung W-Y, Clark CM, Heyman AL, Tratter JA, Eisenmenger JP, Gilbert JR, Lee JE, Alberts MJ, Dawson DV, Bartleit RJ, Earl NL, Siddique T, Vance JM, Conneally PM, Roses AD (1988) Genetic linkage studies in Alzheimer disease families. Exp Neurol 102: 271–279PubMedCrossRefGoogle Scholar
  37. Podlisny MB, Lee G, Selkoe DJ (1987) Gene dosage of the amyloid beta precursor protein in Alzheimer’s disease. Science 238: 669–671PubMedCrossRefGoogle Scholar
  38. Quarrell OWJ, Meredith AL, Tyler A, Yongman S, Upadhyaya M, Harper PS (1987) Exclusion testing for Huntington’s disease in pregnancy with a closely linked DNA marker. Lancet 1: 1281–1283PubMedCrossRefGoogle Scholar
  39. Roll-Hansen N (1988) The progress of eugenics: growth of knowledge and change in ideology. Hist Sci 26: 295–331PubMedGoogle Scholar
  40. Schellenberg GD, Bird TD, Wisjman EM, Moore DK, Boehnke M, Bryant EM, Lampe TH, Nochlin D, Sumi SM, Deeb SS, Beyreuther K, Martin GM (1988) Absence of linkage of chromosome 21q21 markers to familial Alzheimer’s disease. Science 241: 1507–1510PubMedCrossRefGoogle Scholar
  41. Sjogren T, Sjogren H, Lindgren AGH (1952) Morbus Alzheimer and Morbus Pick. A genetic, clinical and patho-anatomical study. Acta Psychiatr Scand [Supp] 82Google Scholar
  42. St. George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, Growdon J, Bruni A, Foncin J-F, Salmon D, Fromelt P, Amaducci L, Sorbi S, Oiacentini S, Stewart GD, Hobbs WJ, Conneally M, Gusella JF (1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235: 885–890PubMedCrossRefGoogle Scholar
  43. Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St. George-Hyslop, PH, Van Keurin ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid B protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235 (4791): 880–884PubMedCrossRefGoogle Scholar
  44. Tanzi R, Haines J, Watkins P, Stewart G, Wallace R, Hallewell R, Wong C, et al. (1988) Genetic linkage map of human chromosome 21. Genomics 3: 129–136PubMedCrossRefGoogle Scholar
  45. Volkers WS, Went LN, Vetger van der Lis M, Harper PS (1980) Genetic linkage studied in Huntington’s Chorea. Annals of Human Genetics 44: 75–79PubMedCrossRefGoogle Scholar
  46. Warren AC, Robakis NK, Ramakrishna N, Koo EH, Ross CA, Robb AS, Folstein MF, Price DL, Antonarakis SE (1987) Beta-amyloid gene is not present in three copies in autopsy validated Alzheimer’s disease, Genomics 1: 307–312PubMedCrossRefGoogle Scholar
  47. Weatherall D (1985) The new genetic and clinical practice, 2nd edn. Oxford University Press, Oxford, p. 206Google Scholar
  48. Whalley WL, Carothers AD, Collyer S, De Mey R, Frackiewicz A (1982) A study of familial factors in Alzheimer’s disease. Br J Psychiatry 140: 249–256PubMedCrossRefGoogle Scholar
  49. Wright AF (1990) The genetics of common forms of dementia. In: McGuffin P, Murray RM (eds) The new genetics. Heinemann, LondonGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • P. McGuffin
  • M. Sargeant
  • G. Weppner

There are no affiliations available

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