Extended Kindreds as a Model for Research on Alzheimer’s Disease

  • J.-F. Foncin
  • D. Salmon
  • A. C. Bruni
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)


This chapter reviews the methods used to gather, organize and analyse the data, and explains how we used the information provided by large kindreds in which Alzheimer’s disease occurs with very high incidence, drawing primarily from our experience with a southern Italian extended family (family “N”). About 4000 subjects, 60 of whom were affected with Alzheimer’s disease, are identified in this pedigree, with the common ancestor of all affected subjects being identified as a woman born in 1715. Exploration of municipal and parish records on a blanket basis was fundamental to establish the pedigree, mental (state) hospital records were used to establish diagnosis, and Bayesian probabilities permitted an estimate of status for subjects for whom age at death was known and genotype probability was known or estimated. Segregation ratio and thence mode of transmission may be established within narrow confidence limits from large bias-free pedigrees; these are the only ones for which Mendelian dominant autosomal transmission, to the exclusion of environmental effects, has been established. Large pedigrees have been decisive in recent progress in the molecular genetics of Alzheimer’s disease. The nosological relationship between the disease expressed in those kindreds and that appearing sporadically or in small clusters is a matter under discussion. What seems certain is that large kindreds are one of the most powerful models at our disposal for research on Alzheimer’s disease.


Segregation Ratio Bayesian Probability Large Pedigree Large Kindred Gerstmann Straussler Scheinker Disease 
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  1. Bayes T (1763) Essay toward solving a problem in the doctrine of chances. Phil Trans (London); reprinted in Bioimetrika (1958) 45: 293–315Google Scholar
  2. Boellaard JN, Schlote W (1980) Subakute spongiforme Encephalopathie mit multiforme Plaquen-bildung: „Eigenartige familiär-hereditäre Krankheit des Zentralnervensystems (spinocerebellare Atrophie mit Demenz, Plaques und plaqueähnüchen Ablagerungen im Klein- und Großhirn“ (Gerstmann, Sträussler, Scheinker). Acta Neuropathol (Berl) 49: 205–212CrossRefGoogle Scholar
  3. Breitner JCS (1985) Dementia of the Alzheimer type: methodological comments. Psychiatry Res 16: 263–264PubMedCrossRefGoogle Scholar
  4. Breitner JCS, Folstein MF (1984) Familial Alzheimer dementia: a prevalent disorder with specific clinical features. Psycholog Med 14: 63–71CrossRefGoogle Scholar
  5. Breitner JCS, Folstein MF (1984) Familial nature of Alzheimer’s disease. N Engl J Med 14: 63–80Google Scholar
  6. 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
  7. Breitner JCS, Murphy EA, Folstein MF (1986) Familial aggregation in Alzheimer dementia. II: Clinical genetic implications of age-dependent onset. J Psychiatr Res 20: 44–45Google Scholar
  8. Breitner JCS, Silverman JM, Mohs RC, Davis KL (1988) Familial aggregation in Alzheimer’s disease: Comparison of risk among relatives of early– and late-onset cases, and among male and female relatives in successive generations. Neurology 38: 207–212PubMedGoogle Scholar
  9. Bruni AC, Salmon D, Montesi MP, Foncin JF (1987) Malattia di Alzheimer familiare: progressi di uno studio. Atti XXV Congresso Nazionale délia Società Italiana di NeurologiaGoogle Scholar
  10. Chase GA, Folstein MF, Breitner JCS, Beaty TH, Self SG (1983) The use of life tables and survival analysis in testing genetic hypotheses, with an application to Alzheimer’s disease. Am J Epidemiol 117: 590–597PubMedGoogle Scholar
  11. Clemenceau S, Foncin J-F, Muller JY, Halle L, Hauptmann G, Seger J, Salmon Ch (1986) Absence de liaison entre la maladie d’Alzheimer et les marqueurs du complément. CR Acad Sc Paris Série III, 303: 149–154Google Scholar
  12. Constantinidis J (1965) L’incidence familiale des lésions cérébrales vasculaires et dégénératives de l’âge anvancé. L’Encéphale 54: 204–239PubMedGoogle Scholar
  13. Crow JF, Mange AP (1965) Measurement of inbreeding from the frequency of marriages between persons of the same surname. Eugenics Q 12: 199–203Google Scholar
  14. Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman DE (1987) Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 325:783–786PubMedCrossRefGoogle Scholar
  15. Elston RC, Stewart J (1971) A general model for the genetic analysis of pedigree data. Hum Hered 21: 523–542PubMedCrossRefGoogle Scholar
  16. Feldman RG, Chandler KA, Levy LL, Glaser GH (1963) Familial Alzheimer’s disease. Neurology 13: 1402–1421Google Scholar
  17. Folstein MF, Breitner JCS (1982) Language disorder predicts familial Alzheimer’s disease. Aging 19: 197–205Google Scholar
  18. Foncin J-F, Cardot JL, Martinet Y, Arnott G (1982) Maladie de Gerstmann-Sträussler-Scheinker: étude anatomo-clinique et généalogique. Rev Neurol (Paris) 138: 123–135Google Scholar
  19. Foncin J-F, Le Beau J (1965) Ultrastructure des plaques séniles. Rev Neurol (Paris) 112: 61–62Google Scholar
  20. Foncin J-F, Supino-Viterbo V (1973) Maladie d’Alzheimer familiale: histopathologic ultrastructurale, étude généalogique. International Congress of Neurology, Barcelona. Excerpta Medica International Congress Series 296: 63–64Google Scholar
  21. Foncin J-F, 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
  22. Foncin J-F, Salmon D, Supino Viterbo V, Feldman RG, Macchi G, Mariotti P, Scoppetta C, Caruso G, Bruni AC (1985) Démence présénile d’Alzheimer transmise dans une famille étendue. Rev Neurol (Paris) 141: 194–202Google Scholar
  23. Frommelt P, Schnabel R, Manz F, Nee L, Polinsky RJ (1987) Neuropathological heterogeneity within a family with dominantly inherited Alzheimer’s disease. International Symposium on Alzheimer’s disease, Amsterdam, 7–9 MayGoogle Scholar
  24. Furuya H, Sasaki H, Goto I, Wong CW, Glenner GG, Sakaki Y (1988) Amyloid B protein gene duplication is not common in Alzheimer’s disease: analysis by polymorphic restriction fragments. Biochem Biophys Res Commun 150: 75–81PubMedCrossRefGoogle Scholar
  25. Gonatas NK, Gambetti P (1970) The pathology of the synapse in Alzheimer’s disease. In: Wolstenholme GEW, O’Connor M (eds) Alzheimer’s disease and related conditions. Churchill, London, pp 169–180Google Scholar
  26. Goudsmit J, White BJ, Weitkamp LR, Keats BJB, Morrow CH, Gajdusek DC (1981) Familial Alzheimer’s disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study. J Neurol Sc 49: 79–89CrossRefGoogle Scholar
  27. Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakagushi AY, Yong AB, Shoulson I, Bonilla E, Martin JB (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306: 234–238PubMedCrossRefGoogle Scholar
  28. Harper PS (1977) Mendelian inheritance or transmissible agent? The lesson of Kuru and the Australia antigen. J Med Genet 14: 379–398Google Scholar
  29. Heston LL, Mastri AR (1977) The genetics of Alzheimer’s disease. Associations with hematologic malignancy and Down’s syndrome. Arch Gen Psychiatry 34: 976–981PubMedGoogle Scholar
  30. Heston LL, White J (1978) Pedigrees of 30 families with Alzheimer’s disease: association with defective organisation of microfilaments and microtubules. Behav Genet 8: 315–331PubMedCrossRefGoogle Scholar
  31. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733–736PubMedCrossRefGoogle Scholar
  32. Knesevich JW, Toro FR, Morris JC, LaBarge E (1985) Aphasia, family history, and the longitudinal course of senile dementia of the Alzheimer type. Psychiatry Res 14: 255–264PubMedCrossRefGoogle Scholar
  33. Knesevich JW (1985) The author replies. Psychiatry Res 16: 263–264CrossRefGoogle Scholar
  34. Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31:312–321PubMedCrossRefGoogle Scholar
  35. Landre MF, Vallat MT, Jutier P (1972) Reconnaissance automatique des liens de paranté. Tracé automatique d’arbre généalogique. MIS 10 Villeurbanne, SIMEPGoogle Scholar
  36. Muller JY, Clemenceau S, Foncin J-F, Salmon D, Halle L, Castellano F, Salmon Ch (1986) Absence de liaison entre la maladie d’Alzheimer et le système HLA. CR Acad Sc Paris. Serie III, 303: 105–108Google Scholar
  37. Murdoch GH, Manuelidis L, Kim JH, Manuelidis EE (1988) Beta-amyloid gene dosage in Alzheimer’s disease. Nucleic Acid Res 16: 357PubMedCrossRefGoogle Scholar
  38. Nee LE, Eldridge R, Sunderland T, Thomas CB, Katz D, Thompson KE, Weingartner H, Weiss H, Julian C, Cohen R (1987) Dementia of the Alzheimer type: clinical and family study of 22 twin pairs. Neurology 37: 359–363PubMedGoogle Scholar
  39. Nee LE, Polinsky RJ, Eldridge R, Weingartner J, Smallberg S, Ebert M (1983) A family with histologically confirmed Alzheimer’s disease. Arch Neurol 40: 203–208PubMedGoogle Scholar
  40. Polinsky RJ, Noble H, Di Chiro G, Nee LE, Feldman RG, Brown RT (1987) Dominantly inherited Alzheimer’s disease: cerebral glucose metabolism. J Neurol Neurosurg Psychiatry 50: 752–757PubMedCrossRefGoogle Scholar
  41. Pro JD, Sumi M, Smith CH (1979) Amyloid plaques in the cerebellum in presenile familial Alzheimer’s disease. Neurology 29: 538–539Google Scholar
  42. Sjögren T, Sjögren H, Lindgren H (1952) A genetic study of Morbus Alzheimer and Morbus Pick. Acta Psychiatr Scand 82: [Suppl 9]Google Scholar
  43. Schellenberg GD, Deeb SS, Boehnke M, Bryant EM, Martin GM, Lampe TH, Bird TD (1987) Association of an apolipoprotein CII allele with familial dementia of Alzheimer type. J Neurogenetic 4: 97–108Google Scholar
  44. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers R, Feldman RG, Pollen D, Drachman D, Growdon J, Bruni A, Foncin J-F, Salmon D, Frommelt P, Amaducci L, Sorbi S, Piacentini S, Stewart GD, Hobbs WJ, Conneally PM, Gusella JF (1987a) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235: 885–890CrossRefGoogle Scholar
  45. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Neve RL, Pollen D, Drachman D, Growdon J, Cupples LA, Nee L, Myers R, O’Sullivan D, Watkins PC, Amos JA, Deutsch CK, Bodfish JW, Kinsbourae M, Feldman RG, Bruni A, Amaducci L, Foncin J-F, Gusella JF (1987b) Absence of duplication of chromosome 21 genes in familial and sporadic Alzheimer’s disease. Science 238: 664–666CrossRefGoogle Scholar
  46. Tanzi RE, St George-Hyslop PH, Haines JL, Polinsky RJ, Nee L, Foncin J-F, Neve RL, McClathey AI, Conneally PM, Gusella JF (1987) The genetic defect in familial Alzheimer’s disease is not tightly linked to the amyloid beta-protein gene. Nature 329:156–157PubMedCrossRefGoogle Scholar
  47. Terry RD, Wisniewski H (1970) The ultrastructure of the neurofibrillary tangle and the senile plaque. In: Wolstenholme GEW, O’Connor M (eds) Alzheimer’s disease and related conditions. Churchill, London, pp 145–165Google Scholar
  48. Van Bogaert L, Maere M, De Smedt E (1940) Sur les formes familiales précoces de la maladie d’Alzheimer. Monatschr Psych Neurol 102: 247–301Google Scholar
  49. Van Broeckhoven C, Genthe AM, Vandenberghe A, Horsthemke B, Backhovens H, Raeymaekers P, Van Hul W, Wehnert A, Gheuens J, Cras P, Bryuland M, Martin JJ, Salbaum M, Multhaup G, Masters CL, Beyreuther K, Gurling HMD, Mullan MJ, Holland A, Barton A, Irving N, Williamson R, Richards SJ, Hardy JA (1987) Failure of familial Alzheimer’s disease to segregate with the A4-Amyloid gene in several European families. Nature 329: 153–155PubMedCrossRefGoogle Scholar
  50. Wexler NS, Conneally PM, Houseman D, Gusella JF (1985) A DNA polymorphism for Huntington’s disease marks the future. Arch Neurol 42: 20–24PubMedGoogle Scholar
  51. Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney J, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA, Penchaszadeh GK, Moreno H, Gibbons K, Faryniarz A, Hobbs W, Anderson MA, Bonilla E, Conneally PM, Gusella JF (1987) Homozygotes for Huntington’s disease. Nature 326: 194–197PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • J.-F. Foncin
  • D. Salmon
  • A. C. Bruni

There are no affiliations available

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