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A Nelson-Aalen Estimate of the Incidence Rates of Early-Onset Alzheimer's Disease Associated with the Presenilin-1 Gene

Published online by Cambridge University Press:  29 August 2014

Eng Hock Gui  and
Angus Macdonald
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Abstract

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We analyse, in a probabilistic setting, Newcombe's (1981) life table method of estimating rates of onset of high-penetrance single-gene disorders, and extend this to a counting process model for individual life histories, including movement between risk groups arising from genetic testing and onset in relatives. A key result is that estimates of rates of onset at any age x must be conditioned only on information available when subjects were age x, even though their later life histories might be available to the investigator. This determines the data that must be included in pedigrees. We derive a Nelson-Aalen-type estimate of a function of the rate of onset, and show that when all that is known is that the persons in the study inherited a mutation with probability 1/2, the function estimated is bounded. In practice, the treatment of censored observations or the methods of ascertainment might cause the estimate to exceed this bound, which results in infinite estimates of the rate of onset but might be a useful diagnostic check on the presence of these features. We summarise the literature on mutations in the Presenilin-1 (PSEN-1) gene, associated with early-onset Alzheimer's disease (EOAD), and from published pedigrees we estimate rates of onset of EOAD.

Keywords

Early-Onset Alzheimer's DiseaseNelson-Aalen EstimatePresenilin-1 GenePedigrees
Type
Articles
Information
ASTIN Bulletin: The Journal of the IAA , Volume 32 , Issue 1 , May 2002 , pp. 1 - 42
Copyright
Copyright © International Actuarial Association 2002

References

Aldudo, J., Bullido, M.J., Arbizu, T., Oliva, R. and Valdivieso, F. (1998) Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer's disease. Neuro-science Letters, 240, 174–176.CrossRefGoogle ScholarPubMed
Aldudo, J., Bullido, M.J., Arbizu, T. and Valdivieso, F. (1999) DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease pre-senilin-1 gene: 2 novel mutations. Human Mutation, 14, 433–439.3.0.CO;2-K>CrossRefGoogle Scholar
Andersen, P.K., Borgan, Ø, Gill, R.D. and Keiding, N. (1993) Statistical models based on counting processes. Springer-Verlag, New York.CrossRefGoogle Scholar
Aoki, M., Abe, K., Oda, N., Ikeda, M., Tsuda, T., Kanai, M., Shoji, M., St. George-Hyslop, P.H. and Itoyama, Y. (1997) A presenilin-1 mutation in a family with Alzheimer's disease and distinctive abnormalities on cranial MRI. Neurology, 48, 1118–1120.CrossRefGoogle Scholar
Axelman, K., Basun, H. and Lannfelt, L. (1998) Wide range of onset in a family with Alzheimer's disease and a Hisl63Tyr mutation in the presenilin-1 gene. Archives of Neurology, 55, 698–702.CrossRefGoogle Scholar
Besançon, R., Lorenzi, A., Cruts, M., Radawiec, S., Sturtz, F., Broussolle, E., Chazot, G., Van Broeckhoven, C., Chamba, G. and Vandenberghe, A. (1997) Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification. Human Mutation (Mutation in Brief), 141, online.Google Scholar
Bird, T.D., Levy-Lahad, E., Poorkaj, P., Sharma, V., Nemens, E., Lahad, A., Lampe, T.H. and Schelleńberg, G.D (1996) Wide range in age of onset for chromosome 1-related familial Alzheimer's disease. Annals of Neurology, 40(6), 932–936.CrossRefGoogle ScholarPubMed
Boteva, K., Vitek, M., Mitsuda, H., De Siva, H., Xu, P.-T., Small, G. and Gilbert, J.R. (1996) Mutation analyisis of presenilin 1 gene in Alzheimer's disease. Lancet, 347, 130–131.CrossRefGoogle Scholar
Campion, D., Flaman, J.-M., Brice, A., Hannequin, D., Dubois, B., Martin, C., Moreau, V., Charbonnier, R., Didierjean, O., Tardieu, S., Penet, C., Puel, M., Pasquier, R., Le Doze, F., Bellis, G., Calenda, A., Heilig, R., Martinez, M., Mallet, J., Bellis, M., Clerget-Darpoux, R., Agid, Y. and Frebourg, T. (1995a) Mutations of the presenilin 1 gene in families with early-onset Alzheimer's disease. Human Molecular Genetics, 4(12), 2373–2377.CrossRefGoogle ScholarPubMed
Campion, D., Brice, A., Hannequin, D., Tardieu, S., Dubois, B., Calenda, A., Brun, E., Penet, C., Tayot, I., Martinez, M., Bellis, G., Mallet, J., Agid, Y. and Clerget-Darpoux, F. (1995b) A large pedigree with early-onset Alzheimer's disease: clinical, neuro-pathological, and genetic characterization. Neurology, 45, 80–85.CrossRefGoogle Scholar
Campion, D., Brice, A., Dumanchin, C., Puel, M., Baulac, M., De La Sayette, V., Hannequin, D., Duyckaerts, C., Michon, A., Martin, G., Moreau, V., Penet, C., Martinez, M., Clerget-Darpoux, R., Agid, Y. and Frebourg, T. (1996). A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years. Neuro Report, 7, 1582–1584.Google Scholar
Campion, D., Dumanchin, C., Hannequin, D., Dubois, B., Belliard, S., Puel, M., Thomas-Anterion, C., Michon, A., Martin, C., Charbonnier, F., Raux, G., Camuzat, A., Penet, C., Mesnage, V., Martinez, M., Clerget-Darpoux, F., Brice, A. and Frebourg, T. (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. American Journal of Human Genetics, 65, 664–670.CrossRefGoogle ScholarPubMed
Cervenakova, L., Brown, P., Sandoval, F., Foncin, J-R., Garruto, R., Polincky, R.J., Nee, L. and Goldfarb, L. (1996) Identification of presenilin-1 gene point mutations in early-onset Alzheimer's disease families. American Journal of Human Genetics, 59(Suppl), A252.Google Scholar
Chapman, J., Asherov, A., Wang, N., Treves, T.A., Korczyn, A.D. and Goldfarb, L.G. (1995) Familial Alzheimer's disease associated with S182 codon 286 mutation. Lancet, 346, 1040.CrossRefGoogle ScholarPubMed
Clark, R.F., Hutton, M., Fuldner, R.A., Froelich, S., Karran, E., Talbot, C., Crook, R., Lendon, C., Prihar, G., He, C., Korenblat, K., Martinez, A., Wragg, M., Busfield, R., Behrens, M.I., Myers, A., Norton, J., Morris, J., Mehta, N., Pearson, C., Lincoln, C., Baker, M., Duff, K., Zehr, C., Perez-Tur, J., Houlden, H., Rui, Z. A., Ossa, I., Lopera, R., Arcos, M., Madrigal, L., Collinge, J., Humphreys, C., Ashworth, A., Sarner, S., Fox, N., Harvey, R., Kennedy, A., Roques, P., Cline, R.T., Phillips, C.A., Venter, J.C., Forsell, L., Axelman, K., Lilius, L., Johnston, J., Cowburn, R., Viitanen, M., Winblad, B., Kosik, K., Haltia, M., Poyhonen, M., Dickson, D., Mann, D., Neary, D., Snowdon, J., Lantos, P., Lannfelt, L., Rossor, M., Roberts, G.W., Adams, M.D., Hardy, J. and Goate, A. (Alzheimer's Disease Collaborative Group) (1995) The structure of the presenilin 1 (SI82) gene and identification of six novel mutations in early onset AD families. Nature Genetics, 11, 219–222.CrossRefGoogle Scholar
Crook, R., Verkkoniemi, A., Perez-Tur, I., Mehta, N., Baker, M., Houlden, H., Farrer, M., Hutton, M., Lincoln, S., Hardy, J., Gwinn, K., Somer, M., Paetau, A., Kalimo, H., Ylikoski, R., Pöyhönen, M., Kucera, S. and Haltia, M. (1998) A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature Medicine, 4(4), 452–455.CrossRefGoogle ScholarPubMed
Cruts, M., Backhovens, H., Wang, S.-Y., Van Gassen, G., Theuns, J., De Jonghe, C., Wehnert, A., De Voecht, J., De Winter, G., Cras, P., Bruyland, M., Datson, N., Weissenbach, J., Den Dunnen, J.T., Martin, J.-J., Hendriks, L. and Van Broeckhoven, C. (1995) Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Human Molecular Genetics, 4(12), 2363–2371.CrossRefGoogle ScholarPubMed
Cruts, M., Hendriks, L. and Van Broeckhoven, C. (1996) The presenilin genes: a new gene family involved in Alzheimer's disease. Human Molecular Genetics, 5 (Review), 1449–1455.CrossRefGoogle Scholar
Cruts, M., Van Duijn, C.M., Backhovens, H., Van Den Broeck, M., Wehnert, A., Serneels, S., Sherrington, R., Hutton, M., Hardy, J., St. George-Hyslop, P.H., Hofman, A. and Van Broeckhoven, C. (1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Human Molecular Genetics, 7(1), 43–51.CrossRefGoogle Scholar
Cruts, M. and Van Broeckhoven, C. (1998) Presenilin mutations in Alzheimer's disease. Human Mutation, 11, 183–190.3.0.CO;2-J>CrossRefGoogle ScholarPubMed
Czech, C., Tremp, G. and Pradier, L. (1999). Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Progress in Neurobiology, 60, 363–384.CrossRefGoogle Scholar
Dartigues, J.F. and Letenneur, L. (2000) Genetic epidemiology of Alzheimer's disease. Current Opinion in Neurology, 13, 385–389.CrossRefGoogle ScholarPubMed
De Jonghe, C., Cruts, M., Rogaeva, E.A., Tysoe, C., Singleton, A., Vanderstichele, H., Meschino, W., Dermaut, B., Vanderhoeven, I., Backhovens, H., Vanmechelon, E., Morris, C.M., Hardy, J., Rubinsztein, D.C., St. George-Hyslop, P.H. And Van Broeckhoven, C. (1999) Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Human Molecular Genetics, 8, 1539–1540.CrossRefGoogle ScholarPubMed
Dumanchin, C., Brice, A., Campion, D., Hannequin, D., Martin, C., Moreau, V., Agid, Y., Martinez, M., Clerget-Darpoux, R., Frebourg, T. and The French Alzheimer's Disease Study Group (1998) De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. Journal of Medical Genetics, 35, 672–673.CrossRefGoogle ScholarPubMed
Elandt-Johnson, R.C. (1973) Age-at-onset distribution in chronic diseases. A life table approach to analysis of family data. Journal of Chronic Disability, 26, 529–545.CrossRefGoogle ScholarPubMed
Ezquerra, M., Carnero, C., Blesa, R., Gelpi, J.L., Ballesta, F. and Oliva, R. (1999) A presenilin 1 mutation (Serl69Pro) associated with early-onset AD and myoclonic seizures. Neurology, 52, 566–570.CrossRefGoogle ScholarPubMed
Ezquerra, M., Carnero, C., Blesa, R. and Oliva, R. (2000) A novel presenilin 1 mutation (Leul66Arg) associated with early-onset Alzheimer's disease. Archives of Neurology, 57, 485–488.CrossRefGoogle Scholar
Farlow, M.R., Murrell, J.R., Hulette, C.M. and Ghetti, B. (2000) Hereditary lateral sclerosis and Alzheimer disease associated with mutation at codon 261 of the presenilin (PS1) gene. Neurobiology of Aging, 21(Suppl), S62.CrossRefGoogle Scholar
Finckh, U., Müller-Thomsen, T., Mann, U., Eggers, C., Markseiner, I., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R.M. and Gal, A. (2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. American Journal of Human Genetics, 66, 110–117.CrossRefGoogle ScholarPubMed
Fischer, E.-P. and Berberich, K. (1999) Impact of modern genetics on insurance. Publications of the Cologne Re, No. 42.Google Scholar
Fleming, T.R. and Harrington, D.R. (1991) Counting processes and survival analysis. John Wiley, New York.Google Scholar
Forsell, C., Froelich, S., Axelman, K., Vestling, M., Cowburn, R.F., Lilius, L., Johnston, J.A., Engvall, B., Johansson, K., Dahlkild, A., Ingelson, M., St. George-Hyslop, P.H. and Lannfelt, L. (1997) A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease. Neuroscience Letters, 234, 3–6.CrossRefGoogle ScholarPubMed
Fox, N.C., Kennedy, A.M., Harvey, R.J., Lantos, P.L., Roques, P.K., Collinge, J., Hardy, J., Hutton, M., Stevens, J.M., Warrington, E.K. and Rossor, M.N. (1997) Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic facto. Brain, 120, 491–501.CrossRefGoogle ScholarPubMed
Fraser, P.E., Yang, D-S., Yu, G., Lévesque, L., Nishimura, M., Arawaka, S., Serpell, L.C., Rogaeva, E. and St George-Hyslop, P. (2000) Presenilin structure, function and role in Alzheimer disease. Biochimica et Biophysica Acta, 1502, 1–15.CrossRefGoogle ScholarPubMed
Funato, H., Enya, M., Yoshimura, M., Morishima-Kawashima, M. and Ihara, Y. (1999) Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation. American Journal of Patholology, 155(1), 23–28.CrossRefGoogle Scholar
Gómez-Isla, T., Wasco, W., Pettingell, W.P., Gurubhagavatula, S., Schmidt, S.D., Jondro, P.D., Mcnamara, M., Rodes, L.A., DiBlasi, T., Growdon, W.B., Seubert, P., Schenk, D., Growdon, J.H., Hyman, B.T. and Tanzi, R.E. (1997) A novel presenilin-1 mutation: increased β-amyloid and neurofibrillary changes. Annals of Neurology, 41, 809–813.CrossRefGoogle ScholarPubMed
Gustafson, L.R., Brun, A., Englund, E., Hagnell, O., Nilsson, K., Stensmyr, M., Ohlin, A.-K. and Abrahamson, M. (1998) A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Human Genetics, 102(3), 253–257.CrossRefGoogle ScholarPubMed
Hardy, J. (1997) Amyloid, the presenilins and Alzheimer's disease. Trends in Neuroscience, 20(4), 154–159.CrossRefGoogle ScholarPubMed
Harper, P.S. and Newcombe, R.G. (1992) Age at onset and life table risks in genetic counselling for Huntington's disease. Journal of Medical Genetics, 29, 239–242.CrossRefGoogle ScholarPubMed
Harvey, R.J., Ellison, D., Hardy, J., Hutton, M., Roques, P.K., Collinge, J., Fox, N.C. and Rossor, M.N. (1998) Chromosome 14 familial Alzheimer's disease: the clinical and neuropathological characteristics of a family with a leucine → serine (L250S) substitution at codon 250 of the presenilin 1 gene. Journal of Neurology, Neurosurgery and Psychiatry, 64, 44–49.CrossRefGoogle ScholarPubMed
Heitjan, D.F. (1994) Ignorability in general incomplete-data models. Biometrika, 81, 701–708.CrossRefGoogle Scholar
Higuchi, S., Yoshino, A., Matsui, T., Matsushita, S., Satoh, A., Iimura, T., Ishikawa, M., Arai, H. and Shirakura, K. (2000) A novel PS1 mutation (W165G) in a Japanese family with early-onset Alzheimer's disease. Alzheimer's Reports, 3(4), 227–231.Google Scholar
Hiltunen, M., Helisalmi, S., Mannermaa, A., Alafuzoff, I., Koivisto, A.M., Lehtovirta, M., Pirskanen, M., Sulkava, R., Verkkoniemi, A. and Soininen, H. (2000) Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination? European Journal of Human Genetics, 8, 259–266.CrossRefGoogle Scholar
Hüll, M., Fiebich, B.L., Dykierek, P., Schmidtke, K., Nitzsche, E., Orszagh, M., Deuschl, G., Moser, E., Schumacher, M., Lucking, C., Berger, M. and Bauer, J. (1998) Early-onset Alzheimer's disease due to mutations of the presenilin-1 gene on chromosome 14: a 7-year follow-up of a patient with a mutation at codon 139. European Archives of Psychiatry and Clinical Neurosciences, 248, 123–129.Google ScholarPubMed
Hutton, M., Busfield, F., Wragg, M., Crook, R., Perez-Tur, J., Clark, R.F., Prihar, G., Talbot, C., Phillips, H., Wright, K., Baker, M., Lendon, C., Duff, K., Martinez, A., Houlden, H., Nichols, A., Karran, E., Roberts, G., Roques, P., Rossor, M., Venter, J.C., Adams, M.D., Cline, R.T., Phillips, C.A., Fuldner, R.A., Hardy, J. and Goate, A. (1996) Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease. NeuroReport, 7, 801–805.CrossRefGoogle ScholarPubMed
Ikeda, M., Sharma, V., Mark Sumi, S., Rogaeva, E.A., Poorkaj, P., Sherrington, R., Nee, L., Tsuda, T., Oda, N., Watanabe, M., Aoki, M., Shoji, M., Abe, K., Itoyama, Y., Hirai, S., Schellenberg, G.D., Bird, T.D. and St. George-Hyslop, P.H. (1996) The clinical pheno-type of two missense mutations in the presenilin 1 gene in Japanese patients. Annals of Neurology, 40, 912–917.CrossRefGoogle Scholar
Jacquier, M., Arango, D., Torres, O., Cruts, M., Serrano, M., Matallana, M., Cano, C. and Van Broeckhoven, C. (2000) Presenilin mutations in a Colombian familial and sporadic sample. Neurobiology of Aging, 21(Suppl), S176.CrossRefGoogle Scholar
Jørgensen, P., Bus, C., Pallisgaard, N., Bryder, M. and Jørgensen, A.L. (1996) Familial Alzheimer's disease co-segregates with a Metl46Ile substitution in presenilin-1. Clinical Genetics, 50, 281–286.CrossRefGoogle ScholarPubMed
Kamimura, K., Tanahashi, H., Yamanaka, H., Takahashi, K., Asada, T. and Tabira, T. (1998) Familial Alzheimer's disease genes in Japanese. Journal of the Neurological Sciences, 160, 76–81.CrossRefGoogle ScholarPubMed
Kamino, K., Sato, S., Sakaki, Y., Yoshiiwa, A., Nishiwaki, Y., Takeda, M., Tanabe, H., Nishimura, T., Ii, K., St. George-Hyslop, P.H., Miki, T. and Ogihara, T. (1996) Three mutations of presenilin 1 gene in early-onset Alzheimer's disease families. Neuroscience Letters, 208, 195–198.CrossRefGoogle ScholarPubMed
Klein, J.P. and Moeschberger, M.L. (1997) Survival analysis: Techniques for censored and truncated data. Springer-Verlag, New York.CrossRefGoogle Scholar
Kowalska, A., Forsell, G., Florczak, J., Pruchnik-Wolinska, D., Modestowicz, R., Paprzycki, W., Wender, M. and Lannfelt, L. (1999) A Polish pedigree with Alzheimer's disease determined by a novel mutation in exon 12 of the presenilin 1 gene: clinical and molecular characterization. Folia Neuropathologica, 37(1), 415–424.Google ScholarPubMed
Kwok, J.B.J., Taddei, K., Hallupp, M., Fisher, C., Brooks, W.S., Broe, G.A., Hardy, J., Fulham, M.J., Nicholson, G.A., Stell, R., St. George-Hyslop, P.H., Fraser, P.E., Kakulas, B., Clarnette, R., Relkin, N., Gandy, S.E., Schofield, P.R. and Martins, R.N. (1997) Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuro Report, 8, 1537–1542.Google ScholarPubMed
Kwok, J.B.J., Smith, M.J., Brooks, W.S., Kril, J., Mclean, C., Hallupp, M. and Schofield, P.R. (2000) Variable presentation of Alzheimer's disease and/or spastic paraparesis phenotypes in pedigrees with a novel PS-1 exon 9 gene deletion or exon 9 splice acceptor mutations. Neurobiology of Aging, 21(Suppl), S25.CrossRefGoogle Scholar
Lendon, C.L., Martinez, A., Behrens, I.M., Kosik, K.S., Madrigal, L., Norton, J., Neuman, R., Myers, A., Busfield, R, Wragg, M., Arcos, M., Arango, Viana J.C., Ossa, J., Ruiz, A., Goate, A.M. and Lopera, F. (1997) E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Human Mutation, 10, 186–195.3.0.CO;2-H>CrossRefGoogle Scholar
Macdonald, A.S. (1996) 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. (2000) A mathematical model of Alzheimer's disease and the ApoE gene. ASTIN Bulletin, 30, 69–110.CrossRefGoogle Scholar
Macdonald, A.S. and Pritchard, D.J. (2001) Genetics, Alzheimer's disease and long-term care insurance. North American Actuarial Journal, 5(2), 54–78.CrossRefGoogle Scholar
Martin, J.J., Gheuens, J., Bruyland, M., Cras, P., Vandenberghe, A., Masters, C.L., Beyreuther, K., Dom, R., Ceuterick, G., Lübke, U., Van Heuverswijn, H., De Winter, G. And Van Broeckhoven, C. (1991) Early-onset Alzheimer's disease in 2 large Belgian families. Neurology, 41, 62–68.CrossRefGoogle ScholarPubMed
Morelli, L., Prat, M.I., Levy, E., Mangone, C.A. and Castano, E.M. (1998) Presenilin 1 Metl46Leu variant due to an A → T transversion in an early-onset familial Alzheimer's disease pedigree from Argentina. Clinical Genetics, 53, 469–473.CrossRefGoogle Scholar
Newcombe, R.G. (1981) A life table for onset of Huntington's Chorea. Annals of Human Genetics, 45, 375–385.CrossRefGoogle ScholarPubMed
Palmer, M.S., Beck, J.A., Campbell, T.A., Humphries, C.B., Rogues, P.K., Fox, N.C., Harvey, R., Rossor, M.N. and Collinge, J. (1999) Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset Alzheimer's disease in the U.K. Human Mutation, 13(3), 256.3.0.CO;2-P>CrossRefGoogle Scholar
Pasternak, J.J. (1999) An introduction to human molecular genetics. Fitzgerald Science Press, Bethesda, Maryland.Google Scholar
Perez-Tur, J., Froelich, S., Prihar, G., Crook, R., Baker, M., Duff, K., Wragg, M., Busfield, F., Lendon, C., Clark, R.F., Roques, P., Fuldner, R.A., Johnston, J., Cowburn, R., Forsell, C., Axelman, K., Lllius, L., Houlden, H., Karran, E., Roberts, G.W., Rossor, M., Adams, M.D., Hardy, J., Goate, A., Lannfelt, L. and Hutton, M. (1995) A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. NeuroReport, 7, 297–301.CrossRefGoogle ScholarPubMed
Perez-Tur, J., Croxton, R., Wright, K., Phillips, H., Zehr, C., Crook, R., Hutton, M., Hardy, J., Karran, E., Roberts, G.W., Lancaster, S. and Haltia, T. (1996) A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration, 5, 207–212.CrossRefGoogle ScholarPubMed
Poduslo, S.E., Herring, K. and Neal, M. (1996) A presenilin 1 mutation in an early onset Alzheimer's family: no association with presenilin 2. Neuroreport, 7, 2018–2020.CrossRefGoogle Scholar
Poorkaj, P., Sharma, V., Anderson, L., Nemens, E., Alonso, M.E., Orr, H., White, J., Heston, L., Bird, T.D. and Schellenberg, G.D. (1998) Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Human Mutation, 11, 216–221.3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Prihar, G., Verkkoniem, A., Perez-Tur, J., Crook, R., Lincoln, S., Houlden, H., Somer, M., Paetau, A., Kalimo, H., Grover, A., Myllykangas, L., Hutton, M., Hardy, J. and Haltia, M. (1999) Alzheimer's disease PS-1 exon 9 deletion defined. Nature Medicine, 5, 1090.CrossRefGoogle ScholarPubMed
Queralt, R., Ezquerra, M., Castellvi, M., Lleo, A., Blesa, R. and Oliva, R. (2001) Detection of the presenilin 1 gene mutation (M139T) in early-onset familial Alzheimer's disease in Spain. Neuroscience Letters, 299, 239–241.CrossRefGoogle ScholarPubMed
Ramirez-Dueñas, M.G., Rogaeva, E.A., Leal, C.A., Lin, C., Ramirez-Casillas, G.A., Hernandez-Romo, J.A., St. George-Hyslop, P.H. and Cantu, J.M. (1998) A novel Leul71Pro mutation in presenilin-1 gene in a Mexican family with early-onset Alzheimer disease. Annals Génét, 41(3), 149–153.Google Scholar
Raux, G., Gantier, R., Thomas-Anterion, C., Boulliat, J., Verpillat, P., Hannequin, D., Brice, A., Frebourg, T. and Campion, D. (2000a) Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology, 55, 1577–1579.CrossRefGoogle ScholarPubMed
Raux, G., Gantier, R., Martin, C., Pothin, Y., Brice, A., Frebourg, T. and Campion, D. (2000b) A novel presenilin 1 missense mutation (LI53V) segregating with early-onset autosomal dominant Alzheimer's disease. Human Mutation, 16, 95.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
Reznik-Wolf, H., Treves, T.A., Davidson, M., Aharon-Peretz, J., St. George-Hyslop, P.H., Chapman, J., Korczyn, A.D., Goldman, B. and Friedman, E. (1996a) A novel mutation of presenilin 1 in familial Alzheimer's disease in Israel detected by denaturing gradient gel electrophoresis. Human Genetics, 98, 700–702.CrossRefGoogle ScholarPubMed
Reznik-Wolf, H., Machado, J., Haroutunlan, V., Demarco, L., Walter, G.F., Chapman, Y., Goldman, B., Davidson, M., Johnston, J., Lannfelt, L., Dani, S.U. and Friedman, E. (1996b) Somatic mutational anaylsis of the APP and presenilin 1 genes in Alzheimer's disease patients' brains using denaturing gradient gel electrophoresis (DGGE). Neurobiology of Aging, 17(Suppl), S14.CrossRefGoogle Scholar
Rogaev, E.I., Sherrington, R., Rogaeva, E.A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Piacentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P.E., Rommens, J.M. And St. George-Hyslop, P.H. (1995) Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature, 376, 775–778.CrossRefGoogle Scholar
Romero, I., Jørgensen, P., Bolwig, G., Fraser, P.E., Rogaeva, E., Mann, D., Havsager, A.-M. and Jørgensen, A.L. (1999) A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease. Neuro Report, 10, 2255–2260.Google Scholar
Rossor, M.N., Fox, N.C., Beck, J., Campbell, T.C. And Collinge, J. (1996) Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin-1 gene mutation. Lancet, 347, 1560.CrossRefGoogle Scholar
Russo, C., Schettini, G., Saido, T.C., Hulette, C., Lippa, C., Lannfelt, L., Ghetti, B., Ganbetti, P., Tabaton, M. and Teller, J.K. (2000) Presenilin-1 mutations in Alzheimer's disease. Nature, 405, 531–532.CrossRefGoogle ScholarPubMed
St. George-Hyslop, P.H. (1998) Role of genetics in tests of genotype, status, arid disease progression in early-onset Alzheimer's disease. Neurobiology of Aging, 19(2), 133–137.CrossRefGoogle Scholar
St. George-Hyslop, P.H. (2000) Molecular genetics of Alzheimer's disease. Biological Psychiatry, 47, 183–199.CrossRefGoogle ScholarPubMed
Sandbrink, R., Zhang, D., Schaeffer, S., Masters, C.L., Bauer, J., Förstl, H. and Beyreuther, K. (1996) Missense mutations of the PS-1/S182 gene in German early-onset Alzheimer's disease patients. Annals of Neurology, 40(2), 265–266.CrossRefGoogle ScholarPubMed
Sato, S., Kamino, K., Miki, T., Doi, A., Li, K., St. George-Hyslop, P.H., Ogihara, T. and Sakaki, Y. (1998) Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease. Human Mutation, Suppl, 591–594.Google Scholar
Sherrington, R., Rogaev, E.I., Liang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.-F., Brum, A.C., Montesi, M.P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R.J., Wasco, W., Da Silva, H.A.R., Haines, J.L., Pericak-Vance, M.A., Tanzi, R.E., Roses, A.D., Fraser, P.E., Rommens, J.M. and St. George-Hyslop, P.H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature, 375, 754–760.CrossRefGoogle ScholarPubMed
Smith, M.J., Gardner, R.J.M., Knight, M.A., Forrest, S.M., Beyreuther, K., Storey, E., Mclean, C.A., Cotton, R.G.H., Cappal, R., And Masters, C.L. (1999) Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene. NeuroReport, 10, 503–507.CrossRefGoogle ScholarPubMed
Smith, M.J., Kwok, J.B.J., Mclean, C.A., Kril, J.J., Broe, G.A., Nicholson, G.A., Cappai, R., Hallupp, M., Cotton, R.G.H., Masters, C.L., Schofield, P.R. and Brooks, W.S. (2001) Variable phenotype of Alzheimer's disease with spastic paraparesis. Annals of Neurology, 49, 125–129.3.0.CO;2-1>CrossRefGoogle ScholarPubMed
Sorbi, S., Nacmias, B., Forleo, P., Piacentini, S., Sherrington, R., Rogaev, E., St. George-Hyslop, P.H. and Amaducci, L. (1995) Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet, 346, 439–440.CrossRefGoogle ScholarPubMed
Steiner, H., Revesz, T., Neumann, M., Romig, H., Grim, M.G., Pesold, B., Kretzsch-Mar, H.A., Hardy, J., Holton, J.L., Baumeister, R., Houlden, H. and Haass, C. (2001) A pathogenic presenilin-1 deletion causes abberant A-beta-42 production in the absence of congophilic amyloid plaques. Journal of Biological Chemistry, 276(46), 7233–7239.CrossRefGoogle Scholar
Strachan, T. and Read, A.P. (1999) Human molecular genetics, second edition. BIOS Scientific Publishers, Oxford.Google Scholar
Subramanian, K., Lemaire, J., Hershey, J.C., Pauly, M.V., Armstrong, K. and Asch, D.A. (2000) Estimating adverse selection costs from genetic testing for breast and ovarian cancer: The case of life insurance. Journal of Risk and Insurance, 66, 531–550.CrossRefGoogle Scholar
Sugiyama, N., Suzuki, K., Matsumura, T., Kawanishi, C., Onishi, H., Yamada, Y., Iseki, E. and Kosaka, K. (1999) A novel missense mutation (G209P) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease. Human Mutation, 14(1), 90–93.3.0.CO;2-S>CrossRefGoogle Scholar
Taddei, K., Kwok, J.B.J., Kril, J.J., Halliday, G.M., Creasey, H., Hallupp, M., Fisher, C., Brooks, W.S., Chung, C., Andrews, C., Masters, C.L., Schofield, P.R. and Martins, R.N. (1998) Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. NeuroReport, 9, 3335–3339.CrossRefGoogle ScholarPubMed
Tanahashi, H., Mitsunaga, Y., Takahashi, K., Tasaki, H., Watanabe, S. and Tabira, T. (1995) Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet, 346, 440.CrossRefGoogle ScholarPubMed
Tanahashi, H., Kawakatsu, S., Kaneko, M., Yamanaka, H., Takahashi, K. and Tabira, T. (1996) Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients. Neuroscience Letters, 218, 139–141.CrossRefGoogle ScholarPubMed
Tedde, A., Forleo, P., Nacmias, B., Piccini, C., Bracco, L., Piacentini, S. and Sorbi, S. (2000) A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset. Neurology, 55, 1590–1591.CrossRefGoogle Scholar
Terreni, L., Valeria, G., Calella, A.M., Gavazzi, A., Alberoni, M., Grimaldi, L.M., Mariani, C. and Forloni, G. (2000) A novel missense mutation (L219F) in exon 8 of the presenilin 1 gene in an Italian family with presenile familial Alzheimer's disease. Neurobiology of Aging, 21(Suppl), S176–S177.CrossRefGoogle Scholar
Tysoe, G., Whittaker, J., Xuereb, J., Cairns, N.J., Cruts, M., Van Broeckhoven, G., Wilcock, G. and Rubinsztein, D.C. (1998) A presenilin-1 truncating mutation is present in ten cases with autopsy-confirmed early-onset Alzheimer's disease. American Journal of Human Genetics, 62, 70–76.CrossRefGoogle Scholar
Verkkoniemi, A., Somer, M., Rinne, J.O., Myllykangas, L., Crook, R., Hardy, J., Viitanen, M., Kalimo, H. and Haltia, M. (2000) Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology, 54, 1103–1109.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
Wasco, W., Pettingell, W.P., Jondro, P.D., Schmidt, S.D., Gurubhagavatula, S., Rodes, L., Diblasi, T., Romano, D.M., Guenette, S.Y., Kovacs, D.M., Growdon, J.H. and Tanzi, R.E. (1995) Familial Alzheimer's chromosome 14 mutations. Nature Medicine, 1(9), 848.CrossRefGoogle ScholarPubMed
Wisniewski, T., Dowjat, W.K., Buxbaum, J.D., Khorkova, O., Efthimiopoulos, S., Kulczycki, J., Lojkowska, W., Weigiel, J., Wisniewski, H.M. and Frangione, B. (1998) A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years. Neuro Report, 9,217–221.Google Scholar
Yasuda, M., Maeda, K., Ikejiri, Y., Kawamata, T., Kuroda, S. and Tanaka, C. (1997) A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy. Neuroscience Letters, 232, 29–32.CrossRefGoogle Scholar
Yasuda, M., Maeda, K., Hashimoto, M., Yamashita, H., Ikejiri, Y., Bird, T.D., Tanaka, C. and Schellenberg, G.D. (1999) A pedigree with a novel presenilin mutation at a residue that is not conserved in presenilin 2. Archives of Neurology, 56, 65–69.CrossRefGoogle Scholar
Yasuda, M., Maeda, S., Kawamata, T., Tamaoka, A., Yamamoto, Y., Kuroda, S., Maeda, K. and Tanaka, C. (2000) Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy. Journal of Neurology, Neurosurgery and Psychiatry, 68, 220–223.CrossRefGoogle ScholarPubMed
Younkin, S., Scheuner, D., Song, X., Eckman, G., Citron, M., Suzuki, N., Bird, T.D., Hardy, J., Hutton, M., Lannfelt, L., Levy-Lahad, E., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Viitanen, M., Wasco, W. and Selkoe, D. (1996) The presenilin 1 and 2 mutations linked to familial Alzheimer's disease increase the extracelluar concentration of amyloid β protein (Aβ) ending at Aβ42(43). Neurobiology of Aging, 17, S38 Abstract.CrossRefGoogle Scholar