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A Mathematical Model of Alzheimer's Disease and the Apoe Gene

Published online by Cambridge University Press:  29 August 2014

Angus Macdonald  and
Delme Pritchard
Angus Macdonald*
Affiliation:
Heriot-Watt University, Edinburgh
Delme Pritchard*
Affiliation:
Heriot-Watt University, Edinburgh
*
Department of Actuarial Mathematics and Statistics, Heriot-Watt UniversityEdinburgh EH14 4AS, United Kingdom.
Department of Actuarial Mathematics and Statistics, Heriot-Watt UniversityEdinburgh EH14 4AS, United Kingdom.
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Abstract

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Alzheimer's disease (AD) accounts for a significant proportion of long-term care costs. The recent discovery that the ε4 allele of the ApoE gene indicates a predisposition to earlier onset of AD raises questions about the potential for adverse selection in long-term care insurance, about long-term care costs in general, and about the potential effects on costs of gene therapy, or better targetted treatments for AD. This paper describes a simple Markov model for AD, and the estimation of the transition intensities from the medical and epidemiological literature.

Keywords

Alzheimer's DiseaseApolipoprotein E GeneGeneticsMarkov Models
Type
Articles
Information
ASTIN Bulletin: The Journal of the IAA , Volume 30 , Issue 1 , May 2000 , pp. 69 - 110
Copyright
Copyright © International Actuarial Association 2000

References

Barclay, L.L., Zemcov, A., Blass, J.P. and McDowell, F.H. (1985a) Factors associated with duration of survival in Alzheimer's disease. Biological Psychiatry 20, 86–93.CrossRefGoogle ScholarPubMed
Barclay, L.L., Zemcov, A., Blass, J.P. and Sansone, J. (1985b) Survival in Alzheimer's disease and vascular dementias. Neurology 35, 834–840.CrossRefGoogle ScholarPubMed
Basun, H., Grut, M., Winblad, B. and Lannfeldt, L. (1995) Apolipoprotein ϵ4 allele and disease progression in patients with late onset Alzheimer's disease. Neuroscience Letters 183, 32–34.CrossRefGoogle ScholarPubMed
Beard, C.M., Kokmen, E., O'Brien, P.C. and Kurland, L.T. (1994) Are patients with Alzheimer's disease surviving longer in recent years? Neurology 44, 1869–1871.CrossRefGoogle ScholarPubMed
Berg, L., Miller, J.P., Storandt, M., Duchek, J., Morris, J.C., Rubin, E.H., Burke, W.J. and Coben, L.A. (1988) Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment. Annals of Neurology 23, 477–484.CrossRefGoogle ScholarPubMed
Bickeböller, H., Campion, D., Brice, A., Amouyel, P., Hannequin, D., Didierjean, O., Penet, C., Martin, C., Pérez-Tur, J., Michon, A., Dubois, B., Ledoze, F., Thomas-Anterion, C., Pasquier, F., Puel, M., Demonet, J-F., Moreaud, O., Babron, M-C., Meulien, D., Guez, D., Chartier-Harlin, M-C., Frebourg, T., Agid, Y., Martinez, M. and Clerget-Darpoux, F. (1997) Apolipoprotein E and Alzheimer's disease: genotypespecific risks by age and sex. American Journal of Human Genetics 60, 439–446.Google ScholarPubMed
Bonaiuto, S., Mele, M., Galluzo, L. and Giannandrea, E. (1995) Survival and dementia: A 7-year follow up of an Italian population. Archives of Gerontology and Geriatrics 20, 105–113.CrossRefGoogle Scholar
Bracco, L., Gallato, R., Grigoletto, F., Lippi, A., Lepore, V., Bino, G., Lazzaro, M.P., Carella, F., Piccolo, T., Pozzilli, C., Giometto, B. and Amaducci, L. (1994) Factors affecting course and survival in Alzheimer's disease. Archives of Neurology 51, 1213–1219.CrossRefGoogle ScholarPubMed
Breteler, M.B.B., Claus, J.J., Van Duijn, C.M., Launer, L.J. and Hofman, A. (1992) Epidemiology of Alzheimer's disease. Epidemiologic Reviews 14, 59–82.CrossRefGoogle ScholarPubMed
Brindle, N., Song, Y., Rogaeva, E., Premkumar, S., Levesque, G., Yu, G., Ikeda, M., Nishimura, M., Paterson, A., Sorbi, S., Duara, R., Farrer, L. and St George-Hyslop, P. (1998) Analysis of the butyrycholinesterase gene and nearby chromosome 3 markers in Alzheimer's disease. Human Molecular Genetics 7, 933–935.CrossRefGoogle Scholar
Burns, A., Lewis, G., Jacoby, R. and Levy, R. (1991) Factors affecting survival in Alzheimer's disease. Psychological Medicine 21, 363–370.CrossRefGoogle ScholarPubMed
Clayton, D. and Hills, M. (1993) Statistical methods in epidemiology. Oxford University Press.Google Scholar
Conte, S.D. and De Boor, C. (1972) Elementary numerical analysis. McGraw-Hill, New York.Google Scholar
Copeland, J.R.M., Davidson, I.A., Dewey, M.E., Gilmore, C., Larkin, B.A., McWilliam, C., Saunders, P.A., Scott, A., Sharma, V. and Sullivan, C. (1992) Alzheimer's disease, other dementias, depression and pseudo-dementia: prevalence, incidence and three-year outcome in Liverpool. British Journal of Psychiatry 161, 230–239.CrossRefGoogle Scholar
Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Rimmler, J.B., Locke, P.A., Conneally, P.M., Schmader, K.E., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer's disease. Nature Genetics 7, 180–184.CrossRefGoogle Scholar
Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Rimmler, J.B., Locke, P.A., Conneally, P.M., Schmader, K.E., Tanzi, R.E., Gusella, J.F., Small, G.W., Roses, A.D., Pericak-Vance, M.A. and Haines, J.L. (1995) Apolipoprotein E, survival in Alzheimer's disease and the competing risks of death and Alzheimer's disease. Neurology 45, 1323–1328.CrossRefGoogle ScholarPubMed
Diesfeldt, H.F.A., Van Houte, L.R. and Moerkens, R.M. (1986) Duration of survival in senile dementia. Acta Psychiatr Scandinavica 73, 366–371.CrossRefGoogle ScholarPubMed
Van Dijk, P.T.M., Dippel, D.W.J., and Habbema, J.Dijk, F. (1991) Survival of patients with dementia. Journal of the American Geriatric Society 39, 603–610.CrossRefGoogle ScholarPubMed
Van Duijn, C.M., de Kniff, P., Wehnert, A., De Voecht, J., Bronzova, J.B., Havekes, L.M., Hofman, A. and Van Broeckhoven, C. (1995) The apolipoprotein E ϵ4 allele is associated with an increased risk of early-onset Alzheimer's disease and a reduced survival. Annals of Neurology 37, 605–610.CrossRefGoogle Scholar
Evans, D.A., Funkenstein, H., Albert, M.S., Scherr, P.A., Cook, N.R., Chown, M.J., Hebert, L.E., Hennekens, C.H. and Taylor, J.O. (1989) Prevalence of Alzheimer's disease in a community population of older persons: Higher than previously reported. Journal of the American Medical Association 262, 2551–2556.CrossRefGoogle Scholar
Evans, D.A., Smith, L.A., Scherr, P.A., Albert, M.S., Funkenstein, H.H. and Hebert, L.E. (1991) Risk of death from Alzheimer's disease in a community population of older persons. American Journal of Epidemiology 134, 403–412.CrossRefGoogle Scholar
Evans, D.A., Beckett, L.A., Field, T.S., Feng, L., Albert, M.S., Bennett, D.A., Tycko, B. and Mayeux, R. (1997) Apolipoprotein E e4 and incidence of Alzheimer's disease in a community population of elder persons. Journal of the American Medical Association 211, 822–824.CrossRefGoogle Scholar
Farrer, L.A., Cupples, L.A., Haines, J.L., Hyman, B., Kukull, W.A., Mayeux, R., Myers, R.H., Pericak-Vance, M.A., Risch, N., Van Duijn, C.M. and Apoe and Alzheimer Disease Meta Analysis Consortium (1997) Effects of age, gender and ethnicity on the association between apolipoprotein E genotype and Alzheimer's disease. Journal of the American Medical Association 278, 1349–1356.CrossRefGoogle Scholar
Forfar, D.O., McCutcheon, J.J. and Wilkie, A.D. (1988) On graduation by mathematical formula. J.I.A. 115, 1–149 and (with discussion) T.F.A. 41, 97–269.Google Scholar
Friedman, L.M., Furberg, C.D. and Demets, D.L. (1998) Fundamentals of clinical trials. Springer-Verlag, New York.CrossRefGoogle Scholar
Frisoni, G.B., Govoni, S., Geroldi, C., Bianchetti, A., Calabres, L., Franceschini, G. and Trabucchi, M. (1995) Gene dose of the ϵ4 allele of apolipoprotein E and disease progression in sporodic late onset Alzheimer's disease. Annals of Neurology 37, 596–604.CrossRefGoogle ScholarPubMed
Gao, S., Hendrie, H.C., Hall, K.S. and Hui, S. (1998) The relationship between age, sex and the incidence of dementia and Alzheimer's disease. Archives of General Psychiatry 55, 809–815.CrossRefGoogle Scholar
Gomez-Isla, T., West, H.L., Rebeck, G.W., Harr, S.D., Gowdon, J.H., Locascio, J.J., Perls, T.T., Lepsitz, L.A. and Hyman, B.T. (1996) Clinical and pathological correlates of apolipoprotein E ϵ4 in Alzheimer's disease. Annals of Neurology 39, 62–70.CrossRefGoogle ScholarPubMed
Green, S., Benedetti, J. and Crowley, J. (1997) Clinical trials in oncology. Chapman and Hall, London.CrossRefGoogle Scholar
Hagnell, O., Ojesjo, L. and Rorsman, B. (1992) Incidence of dementia in the Lundby study. Neuroepidemiology 11, 61–66.CrossRefGoogle ScholarPubMed
Hebert, L.E., Scherr, P.A., Beckett, L.A., Albert, M.S., Pilgrim, D.M., Chown, M.J., Funkenstein, H.H. and Evans, D.A. (1995) Age specific incidence of Alzheimer's disease in a community population. Journal of the American Medical Association 273, 1354–1359.CrossRefGoogle Scholar
Heyman, A., Peterson, B., Fillenbaum, G. and Pieper, C. (1996) The consortium to establish a registry for Alzheimer's disease (CERAD) Part XIV: Demographic and clinical predictors of survival in patients with Alzheimer's disease. Neurology 46, 656–660.CrossRefGoogle Scholar
Heyman, A., Peterson, B., Fillenbaum, G. and Pieper, C. (1997) Predictors of time to institutionalization of patients with Alzheimer's disease: the CERAD experience part XVII. Neurology 48, 1304–1309.CrossRefGoogle ScholarPubMed
Jarvik, G.P., Larson, E.B., Goddard, K., Kukull, W.A., Schellenberg, G.D. and Wijsman, E.M. (1996) Influence of apolipoprotein E genotype on the transmission of Alzheimer's disease in a community-based sample. American Journal of Human Genetics 58, 191–200.Google Scholar
Jorm, A.F. and Jolley, D. (1998) The incidence of dementia – a meta analysis. Neurology 51, 728–733.CrossRefGoogle ScholarPubMed
Jost, B.C. and Grossberg, G.T. (1995) The natural history of Alzheimer's disease: a brain bank study. Journal of the American Geriatrics Society 43, 1248–1255.CrossRefGoogle ScholarPubMed
Kahn, H. and Sempos, C.T. (1989) Statistical methods in epidemiology. Oxford University Press.Google Scholar
Kokmen, E., Chandra, V. and Schoenberg, B. (1988) Trends in incidence of dementing illness in Rochester, Minnesota, in three quinquennial periods, 1960–1974. Neurology 38, 975–980.CrossRefGoogle ScholarPubMed
Kokmen, E., Beard, R.N., O'Brien, P.C., Offord, M.S. and Kurland, L.T. (1993) Is the incidence of dementing illness changing? Neurology 43, 1887–1892.CrossRefGoogle ScholarPubMed
Kuusisto, J., Koivisto, K., Mykkänen, L., Helkala, E-L., Vanhanen, M., Hänninen, T., Pyörälä, K., Kesäniemi, Y.A., Riekkinon, P. and Laakso, K. (1994) Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. British Medical Journal 309, 636–638.CrossRefGoogle ScholarPubMed
Lambert, J-C., Pasquier, F., Cottel, D., Frigard, B., Amouyel, P. and Chartier-Harlin, M-C. (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease, Human Molecular Genetics 7, 533–540.CrossRefGoogle ScholarPubMed
Lehmann, D.J., Johnston, C. and Smith, A.D. (1997) Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. Human Molecular Genetics 6, 1933–1936.CrossRefGoogle ScholarPubMed
Lehtovirta, M., Helisalmi, S., Mannermaa, A., Soininen, H., Koivisto, K., Ryynänen, M. and Riekkinen, Sr P. (1995) Apolipoprotein E polymorphism and Alzheimer's disease in Eastern Finland. Neuroscience Letters 185, 13–15.CrossRefGoogle ScholarPubMed
Lemaire, J., Subramanian, K., Armstrong, K. and Asch, D.A. (2000) Pricing term insurance in the presence of a family history of breast or ovarian cancer. To appear in North American Actuarial Journal.Google Scholar
Letenneur, L., Commences, D., Dartigues, J.F. and Barbergergateau, P. (1994) Incidence of dementia and Alzheimer's disease in elderly community residents of southwestern France. International Journal of Epidemiology 23, 1256–1261.CrossRefGoogle Scholar
Levy-Lahad, E. and Bird, T.D. (1996) Genetic factors in Alzheimer's disease: a review of recent advances. Annals of Neurology 40, 829–840.CrossRefGoogle ScholarPubMed
Liddell, M., Williams, J., Bayer, A., Kaiser, F. and Owen, M. (1994) Confirmation of association between the ϵ4 allele of apolipoprotein E and Alzheimer's disease. Journal of Medical Genetics 31, 197–200.CrossRefGoogle Scholar
Lilienfeld, D.E. and Stolley, P.D. (1994) Foundations of epidemiology. Oxford University Press.CrossRefGoogle Scholar
Lopez, O.L., Lopez-Pousa, S., Kamboh, M.I., Adroer, R., Oliva, R., Lozano-Gallego, M., Becker, T.B. and Dekosky, S.T. (1998) Apolipoprotein E polymorphism in Alzheimer's disease: a comparative study of two research populations from Spain and the United States. European Neurology 39, 229–233.CrossRefGoogle ScholarPubMed
Lucotte, G., David, F., Legrand, C., Turpin, J-C. and Clavel, C. (1997) Predictive value of apolipoprotein E ϵ4 allele genotyping in Alzheimer's disease. Alzheimer's Research 3, 7–9.Google Scholar
Macdonald, A.S. (1996a) An actuarial survey of statistical models for decrement and transition data I: Multiple state, Poisson and binomial models. British Actuarial Journal 2, 129–155.CrossRefGoogle Scholar
Macdonald, A.S. (1996b) An actuarial survey of statistical models for decrement and transition data III: Counting process models. British Actuarial Journal 2, 703–726.CrossRefGoogle Scholar
Macdonald, A.S. (1997) How will improved forecasts of individual lifetimes affect underwriting?. Philosophical Transactions of the Royal Society B, 352, 1067–1075, and (with discussion) British Actuarial Journal 3, 1009–1025 and 1044–1058.CrossRefGoogle ScholarPubMed
Macdonald, A.S. (1999) Modeling the impact of genetics on insurance. North American Actuarial Journal 3:1, 83–101.CrossRefGoogle Scholar
Macdonald, A.S. and Pritchard, D.J. (1999) Genetics, Alzheimer's disease and long-term care insurance. Genetics and Insurance Research Report No. 99/2, Department of Actuarial Mathematics and Statistics, Heriot-Watt University, Edinburgh.Google Scholar
Massullo, C., Daniele, A., Seripa, D., Filippini, V., Gravina, C., Carbone, G., Gainotti, G. and Fazio, V.M. (1998) Apolipoprotein E genotype in sporadic early- and late-onset Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 9, 121–125.CrossRefGoogle Scholar
Mayeux, R., Stern, Y., Ottman, R., Tatemichi, T.K., Tang, M-X., Maestre, G., Ngai, C., Tycko, B. and Ginsberg, H. (1993) The apolipoprotein ϵ4 allele in patients with Alzheimer's disease. Annals of Neurology 34, 752–754.CrossRefGoogle ScholarPubMed
Mölsä, P.K., Marttila, R.J. and Rinnes, U.K. (1982) Epidemiology of dementia in a Finnish population. Acta Neurologica Scandinavica 65, 541–552.CrossRefGoogle Scholar
Mölsä, P.K., Marttila, R.J. and Rinnes, U.K. (1986) Survival and cause of death in Alzheimer's disease and multi-infarct dementia. Acta Neurologica Scandinavica 74, 103–107.CrossRefGoogle ScholarPubMed
Myers, R.H., Schaeffer, E.J., Wilson, P.W.F., D'Agostino, R., Ordovas, J.M., Espino, A., White, R.F., Knoefel, J.E., Cobb, J.L., Mcnulty, K.A., Beiser, A. and Wolf, P.A. (1996) Apolipoprotein E ϵ4 association with dementia in a population based study: the Framingham study. Neurology 46, 673–677.CrossRefGoogle Scholar
Nalbantoglu, J., Gilfix, B.M., Bertrand, P., Robitaille, Y., Gauthier, S., Rosenblatt, D.S. and Poirier, J. (1994) Predictive value of apolipoprotein E genotyping in Alzheimer's disease: results of an autopsy series and an analysis of several combined studies. Annals of Neurology 36, 889–895.CrossRefGoogle Scholar
Nilsson, L.V. (1984) Incidence of severe dementia in an urban sample followed from 70 to 79 years of age. Acta Psychiatrica Scandinavica 70, 478–486.CrossRefGoogle Scholar
Norberg, R. (1995) Differential equations for moments of present values in life insurance. Insurance: Mathematics and Economics 17, 171–180.Google Scholar
Norrman, J., Brookes, A.J., Yates, C. and Clair, D.S. (1995) Apolipoprotein E genotype and its effect on duration and severity of early and late onset Alzheimer's disease. British Journal of Psychiatry 167, 533–536.CrossRefGoogle ScholarPubMed
O'Connor, D.W., Pollitt, P.A., Hyde, J.B.et al. (1989) The prevalence of dementia as measured by the Cambridge Mental Disorders of the Elderly Examination. Acta Psychiatrica Scandinavica 79, 190–198.CrossRefGoogle ScholarPubMed
Ott, A., Breteler, M.M.B., van Harskamp, F., Stijnen, T. and Hofman, A. (1998) Incidence and risk of dementia. American Journal of Epidemiology 147, 574–580.CrossRefGoogle ScholarPubMed
Payami, H., Schellenberg, G.D., Zareparsi, S., Kaye, J., Sexton, G.J., Head, M.A., Matsuyama, S.S., Jarvik, L.F., Miller, B., McManus, D.Q., Bird, T.D., Katzman, R., Heston, L., Norman, D. and Small, G.W. (1997) Evidence for association of HLA-A2 allele with onset age of Alzheimer's disease. Neurology 48, 512–518.CrossRefGoogle Scholar
Pericak-Vance, M.A., Bebout, J.L., Gaskell, P.C., Yamaoka, L.H., Hung, W.Y., Alberts, M.J., Walker, A.P., Bartlett, R.J., Haynes, C.A., Welsh, K.A., Earl, N.L., Heyman, A., Clark, C.M. and Roses, A.D. (1991) Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. American Journal of Human Genetics 48, 1034–1050.Google ScholarPubMed
Pfeffer, R.I., Afifi, A.A. and Chance, J.M. (1987) Prevalence of Alzheimer's disease in a retirement community. American Journal of Epidemiology 125, 420–436.CrossRefGoogle Scholar
Piantadosi, S. (1997) Clinical trials: A methodologicperspective. John Wiley and Sons, New York.Google Scholar
Poduslo, S.E., Neal, M., Herring, K. and Shelly, J. (1998) The apolipoprotein CI A allele as a risk factor for Alzheimer's disease. Neurochemical Research 23. 361–367.CrossRefGoogle Scholar
Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P. and Gauthier, S. (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342, 697–699.CrossRefGoogle ScholarPubMed
Pritchard, D.J. (1997) Life assurance: financial implications of a change in insuring behaviour resulting from individuals' increased knowledge of their genetic predispositions. M.Sc. dissertation, Heriot-Watt University, Edinburgh.Google Scholar
Rocca, W.A., Cha, R.H., Waring, S.C. and Kokmen, E. (1998) Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975–1984. American Journal of Epidemiology 148, 51–62.CrossRefGoogle ScholarPubMed
Rorsman, B., Hagnell, O. and Lanke, J. (1986) Prevalence and incidence of senile and multi-infarct dementia in the Lundby study: a comparison between the time periods 1947–1957 and 1957–1972. Neuropsychobiology 15, 122–129.CrossRefGoogle ScholarPubMed
Roses, A.D. (1995) Apolipoprotein E genotyping in the differential diagnosis, not prediction, of Alzheimer's disease. Annals of Neurology 38, 6–14.CrossRefGoogle Scholar
Sayetta, R.B. (1986) Rates of senile dementia — Alzheimer's type in the Baltimore longitudinal study. Journal of Chronic Disabilities 39, 271–286.CrossRefGoogle ScholarPubMed
Selvin, S. (1996) Statistical analysis of epidemiologic data. Oxford University Press.Google Scholar
Severson, M.A., Smith, G.E., Tangalos, E.G., Peterson, R.C., Kokmen, E., Ivnik, R.J., Atkinson, E.J. and Kurland, L.T. (1994) Patterns and predictors of institutionalization in community-based dementia patients. Journal of the American Geriatrics Society 42, 181–185.Google ScholarPubMed
Singleton, A., Smith, G., Gibson, A.M., Woodward, R., Perry, R.H., Ince, P.G., Edwardson, J.A. and Morris, C.M. (1998) No association between the K variant of the butyrylcholinesterase gene and pathologically confirmed Alzheimer's disease. Human Molecular Genetics 7, 937–939.CrossRefGoogle Scholar
Slooter, A.J.C. and Van Duijn, C.M. (1997) Genetic epidemiology of Alzheimer disease. Epidemiologic Reviews 19, 107–119.CrossRefGoogle ScholarPubMed
Slooter, A.J.C., Cruts, M., Kalmijn, S., Hofman, A., Breteler, M.M.B., Van Broeckhoven, C. and Van Duijn, C.M. (1998) Risk estimates of dementia by apolipoprotein E genotype from a population-based incidence study: the Rotterdam study. Archives of Neurology 55, 964–968.CrossRefGoogle ScholarPubMed
Stern, G., Tang, M.X., Denaro, J. and Mayeux, R. (1995) Increased risk of mortality in Alzheimer's disease patients with more advanced educational and occupational attainment. Annals of Neurology 37, 590–595.CrossRefGoogle ScholarPubMed
Stern, Y., Brandt, J., Albert, M., Jacobs, D.M., Liu, X., Bell, K., Marder, K., Sano, M., Albert, S., Castenada, C.D-C., Bylsma, F., Tycko, B. and Mayeux, R. (1997) The absence of an apolipoprotein ϵ4 allele is associated with a more aggressive form of Alzheimer's disease. Annals of Neurology 41, 615–620.CrossRefGoogle Scholar
Strachan, T. and Read, A.P. (1999) Human molecular genetics (second edition). BIOS Scientific Publishers, Oxford.Google Scholar
Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G.S. and Roses, A.D. (1993) Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type-4 allele in late-onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1977–1981.CrossRefGoogle Scholar
Subramanian, K. and Lemaire, J. (2000) Estimating adverse selection costs in a market with genetic testing for breast and ovarian cancer: the case of life insurance. To appear in Journal of Risk and Insurance.Google Scholar
Tan, K.W. (1997) The financial impact of genetic testing on annuities. M.Sc. dissertation, Heriot-Watt University. Edinburgh.Google Scholar
Tierney, M.C., Fisher, R.H., Lewis, A.J., Zorzitto, M.L., Snow, W.G., Reid, D.W. and Nieuwstraten, P. (1988) The NINCDS-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer's disease: a clinicopathologic study of 57 cases. Neurology 38, 359–364.CrossRefGoogle ScholarPubMed
Treves, T., Korczyn, A.D., Zilber, N., Kahana, E., Leibowitz, Y., Alter, M. and Schoenberg, B.S. (1986) Presenile dementia in Israel. Archives of Neurology 43, 26–29.CrossRefGoogle ScholarPubMed
Tsai, M-S., Tangalos, E.G., Petersen, R.C., Smith, G.E., Schaid, D.J., Kokmen, E., Ivnik, R.J. and Thibodeau, S.N. (1994) Apolipoprotein E: risk factor for Alzheimer's disease. American Journal of Human Genetics 54, 643–649.Google Scholar
Walsh, J.S., Welch, H.G. and Larson, E.B. (1990) Survival of outpatients with Alzheimer-type dementia. Annals of Internal Medicine 113, 429–434.CrossRefGoogle ScholarPubMed
Warren, V., Brett, P., Macdonald, A.S., Plumb, R.H. and Read, A.P. (1999) Genetic tests and future need for long-term care in the UK: report of a Work Group of the Continuing Care Conference Genetic Tests and Long-term Care Study Group. Continuing Care Conference, London.Google Scholar
Waters, H.R. (1984) An approach to the study of multiple state models. Journal of the Institute of Actuaries 111, 363–374.CrossRefGoogle Scholar
Waters, H.R. and Wilkie, A.D. (1987) A short note on the construction of life tables and multiple decrement tables. Journal of the Institute of Actuaries 114, 569–580.CrossRefGoogle Scholar
Waters, H.R. (1991) Computational procedures for the model. Continuous Mortality-Investigation Bureau Report 12, 79–96.Google Scholar