- Email: [email protected]
α-Antichymotrypsin gene polymorphism and risk for Alzheimer's disease in the Spanish population
Neuroscience Letters 240 (1998) 107–109
a-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease in the Spanish population Mario Ezquerra a, Rafael Blesa b, Eduard Tolosa b, Francisca Ballesta a, Rafael Oliva a ,* a
b
Genetic Service, Hospital Clı´nic i Provincial and University of Barcelona, Villarroel 170, Barcelona 08036, Spain Neurology Service, Hospital Clı´nic i Provincial and University of Barcelona, Villarroel 170, Barcelona 08036, Spain Received 3 November 1997; accepted 1 December 1997
Abstract The a-antichymotrypsin (ACT) and the ApoE polymorphisms have been determined in 136 Alzheimer’s disease (AD) patients and in 92 age-matched controls. Only a borderline significant difference is found when comparing the overall ACT/AA genotype frequency between AD patients and controls (x2, P = 0.08). However this difference is attributable entirely and significantly to the ApoE e4 non-carrier AD group (x2, P = 0.004). No differences are found in the ACT/AA genotype frequency of the ApoE e4 AD carrier group as compared controls (x2, P = 0.98) in contrast with previous works. These findings support that the presence of the ACT/AA genotype is a genetic risk factor for developing AD in non-ApoE e4 carriers subjects in our population. 1998 Elsevier Science Ireland Ltd.
Keywords: Alzheimer’s disease; a-Antichymotrypsin; a-Antichymotrypsin polymorphism; Genes; Apolipoprotein E; ApoE
At least four genes are clearly involved in the Alzheimer’s disease pathology at present. Mutations in the presenilin 1 gene (PS-1) [21,26], the presenilin 2 gene (PS-2) [15], and the APP gene [9] are the direct cause for some of the familial and early onset AD cases. The presence of the ApoE e4 allele increases the genetic risk for developing early and late onset AD [2,4,6,16,20,22,25]. Similarly the PS-1 1/1 intronic polymorphism has been found as a risk factor modifier for developing AD [28,7]. However the presence of the ApoE e4 allele or the presence of the PS-1 1/1 intronic polymorphism are neither necessary not sufficient to start the AD pathology. An additional candidate protein potentially involved in the biochemical process leading to the AD pathology is a-antichymotrypsin (ACT) which is a component of the senile plaques found in brains from AD patients [1,3] and binds with a high affinity to b-amyloid protein [8]. Recently it has been reported that the frequency of ACT/A allele and frequency of the ACT/AA genotype are increased in AD patients as compared to controls [12,13,17,24,29]. This correlation has not been found in * Corresponding author. Tel.: +34 3 2275510; fax: +34 3 4035260; e-mail: [email protected]
other studies [6,10,18]. In one work it has been reported that the age of onset may be lowered by the presence of the ACT/AA genotype [23]. In the present work we have evaluated the ACT polymorphism in 136 AD patients (mean age 64.4 ± 9.6) and in 92 age-matched controls (mean age 67 ± 11.8). The patients and controls came from the Hospital Clı´nic of Barcelona. The criteria for inclusion has been described in previous papers from our group [2,4,7]. The DNA was extracted from blood using the DNA direct DynabeadsTM kit. The samples were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) as previous described for ApoE and for ACT [12,27]. After polyacrylamide gel electrophoresis of the restriction enzyme digested PCR products, the bands were stained with ethidium bromide and visualised under UV light and the results recorded photographically. The results were subsequently analysed by the SSPS statistical package. We have found a higher overall ACT/AA genotype frequency in AD patients as compared to controls (41 vs. 27.7%) although at borderline significance (P = 0.08). However after stratification of the AD patients according to the ApoE status it becomes clear that the differences are attributable entirely to the ApoE e4 non-carrier group
0304-3940/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(97) 00924- 5
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M. Ezquerra et al. / Neuroscience Letters 240 (1998) 107–109
Table 1 ACT genotypes and presence or absence of ApoE e4 alleles in Alzheimer’s patients and controls APOE e4 non-carriers (%)
ACT genotypes TT AT AA ACT alleles T A
APOE e4 carriers (%)
AD (n = 71)
Control (n = 78)
AD (n = 65)
Control (n = 14)
16.9 29.6 53.5*
19.2 52.6 28.2
21.5 50.8 27.7
21.4 50.0 28.6
30.7** 69.3
43.3 56.7
46.9 53.1
46.4 53.6
Significant differences as compared to controls: Chi-square test, *P = 0.004, **P = 0.006.
(53.5 vs. 28.2%, P = 0.004; Table 1). The ApoE e4 carrier AD group has a ACT/AA genotype frequency similar to that of the controls and it is not statistically significant (x2, P = 0.98). The odds ratio for developing AD of the ACT/ AA bearers as compared to the non-ACT/AA bearers in the non-ApoE e4 group is 2.93 (OR; 95% confidence interval (CI) = 1.529–5.64). These results are in contrast with those of Kamboh et al. [12] and Yoshiiwa et al. [29] since they found that the ACT/AA genotype is increased just in the ApoE e4 allele carrier group, but are in agreement with the results of Muramatsu et al. [17] who have found in the Japanese population the same effect described here. Some researchers do not find a genetic effect of the ACT polymorphism [6,10,18]. Thus, it is necessary to explain the heterogeneity of the results among the different populations if we assume that the ACT polymorphism really plays a role in the AD pathogenesis. The environmental and genetic factors leading to the development of AD could be different in the different populations studied and therefore the ACT polymorphism could be pathogenic only in association with other unknown genes or environmental factors. Two hypothesises are possible in explaining the effect of ApoE and ACT polymorphisms: (1) that the ACT and the ApoE genes are involved in AD pathogenesis with an additive effect; (2) that the two genes act self-sufficiently as risk factors and are competing for the pathology. Our data is consistent with the second possibility. Further evidence for the existence of two independent mechanisms is provided by the demonstration of a differential effect of the ACT and the ApoE polymorphisms on the blood cerebral flow in AD patients [11]. Alternatively, the ACT polymorphism may be in linkage disequilibrium with another mutation of this gene or another gene nearby explaining the different findings of several researchers. Recently, it has been described a possible association between the PI*M3 allele of the a1-antitrypsin (AAT) and AD [14]. The ACT and the AAT are closely related evolutionary, and encoded by two genes in close neighbourhood on chromosome 14 [5]. Genetic defects in both ACT and AAT have been found to be associated with lung and liver abnormalities [19]. This fact suggests that the two genes could also
have a common mechanism involved in AD pathology. The possibility is now open to search for these additional genetic or environment risk factors interacting or associated with the different ACT polymorphisms. Supported by a grant from the Fondo de Investigaciones FIS96/0658 to R.O. [1] Abraham, C.R., Selkoe, D.J. and Potter, H., Immunochemical identification of serine protease inhibitor a1-antitrypsin in the brain amyloid deposits of Alzheimer’s disease, Cell, 52 (1988) 487–501. [2] Adroer, R., Santacruz, P., Blesa, R., Lopez-Pousa, S., Ascaso, C. and Oliva, R., Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases, Neurosci. Lett., 189 (1995) 182– 186. [3] Bergem, A.L.M. and Lannfelt, L., Apolipoprotein E and the interaction with a1-antichymotrypsin as risk factors in Alzheimer’s disease and vascular dementia, Finding from a twin study, Neurol. Aging, 17 (Suppl. ) (1996) S61. [4] Blesa, R., Adroer, R., Santacruz, P., Ascaso, C., Tolosa, E. and Oliva, R., High apolipoprotein E allele frequency in age related memory decline, Ann. Neurol., 39 (1996) 548–552. [5] Byth, B.C., Billingsley, G.D. and Cox, D.W., Physical and genetic mapping of the serpin gene cluster at 14q32.1: allelic association and unique haplotype associated with a1-antitrypsin deficiency, Am. J. Hum. Genet., 55 (1994) 126–133. [6] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Shmechel, P.C., Gaskell, P.C., Small, G.H., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 261 (1993) 921–923. [7] Ezquerra, M., Blesa, R., Tolosa, E., Lopez Pousa, S., Aguilar, M., Pen˜a, J., Van Broeckhoven, C., Ballesta, F. and Oliva, R., The genotype 2/2 of the presenilin-1 is decreased in Spanish early-onset Alzheimer’s disease, Neurosci. Lett., 227 (1997) 201–204. [8] Fraser, P.E., Nguyen, J.T., McLachlan, D.R., Abraham, C.R. and Kirschener, D.A., a1-antichymotrypsin binding to Alzheimer Ab peptides is sequence specific and induces fibril disagregation in vitro, J. Neurochem., 61 (1993) 298–305. [9] Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease, Nature, 349 (1991) 704–709.
M. Ezquerra et al. / Neuroscience Letters 240 (1998) 107–109 [10] Haines, J.L., Pritchard, M.L., Saunders, A.M., Schildkraut, J.M., Growdon, J.H., Gaskell, P.C., Farrer, L.A., Auerbach, S.A., Gusella, J.F., Locke, P.A., Rosi, M.L., Yamaoka, L., Small, G.W., Conneally, P.M., Roses, A.D. and Pericack-Vance, M.A., No genetic effect of a1-antichymotrypsin in Alzheimer disease, Genomics, 33 (1996) 53–56. [11] Higuchi, M., Arai, H., Nakagawa, T., Higuchi, S., Muramatsu, T., Matsushita, S., Kosaka, Yi., Itho, M. and Sasaki, H., Regional cerebral glucose utilization is modulated by the dosage of apolipoprotein E type 4 allele and alpha (1) antichymotrypsin type A allele in Alzheimer’s disease, NeuroReport, 8 (12 ) (1997) 2639–2643. [12] Kamboh, M.I., Sanghera, D.K., Ferrell, R.E. and DeKosky, S.T., APOE*4 associated Alzheimer’s disease risk is modified by aantichymotrypsin polymorphism, Nature Genet., 10 (1995) 486–488. [13] Kevin, M., Morgan, L., Carpenter, K., Lowe, J., Lam, L., Cave, S., Xuereb, J., Wischik, C., Harrington, C. and Kalsheker, N.A., Microsatellite polymorphism of the a1-antichymotrypsin gene locus associated with sporadic Alzheimer’s disease, Hum. Genet., 99 (1996) 27–31. [14] Kowalska, A., Danker-Hopfe, H., Wender, M., Florczak, J. and Walter, H., Association between the PI*M3 allele of a1-antitrypsin and Alzheimer’s disease?, A preliminary report, Hum. Genet., 98 (1996) 744–746. [15] Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D.M., Oshima, J., Pettingell, W.H., Yu, C., Jondro, P.D., Schmidt, S.D., Wang, K., Crowley, A., Fu, Y., Guerelte, S., Galas, D., Nemens, E., Wijsman, E., Bird, T., Schellenberg, G. and Tanzi, R., Candidate gene for the chromosome 1 familial Alzheimer’s disease locus, Science, 269 (1995) 973–977. [16] Mayeux, R., Stern, Y., Oittman, R., Tatemichi, T.K., Tang, M.X., Maestre, G., Ngai, C., Tycko, B. and Ginsberg, H., The apolipoprotein e4 allele in patients with Alzheimer’s disease, Ann. Neurol., 34 (1993) 752–754. [17] Muramatsu, T., Matsushita, S., Arai, H., Sasaki, H. and Higuchi, S., a-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease, J. Neurol. Trans., 103 (1996) 1205–1210. [18] Nacmias, B., Tedde, A., Latorraca, S., Piacentini, S., Braco, L., Amaducci, L., Guarniere, B.M., Petrucci, C., Ortenzi, L. and Sorbi, S., Apolipoprotein E and a-antichymotrypsin gene polymorphism in Alzheimer’s disease, Ann. Neurol., 40 (1996) 678–680. [19] Poller, W., Faber, J.P., Weidinger, S., Tief, K., Scholtz, S., Fisher, M., Olek, K., Kirchgesser, M. and Heidtmann, H.H., A leucine-to-proline substitution causes a defective a-antichymotrypsinn allele associated with familial obstructive lung disease, Genomics, 17 (3 ) (1993) 740–743.
109
[20] Saunders, A., Strittmatter, W., Schemechel, D., St GeorgeHyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Craper, D.R., Alberts, M.J., Hulette, C., Crain, B., Golgaber, D. and Roses, A.D., Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease, Neurology, 43 (1993) 1467–1472. [21] Sherrington, R., Rogaev, E., Llang, Y., Rogaeva, E.A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.F., Bruni, 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., Cloning a gene bearing missense mutations in early-onset familial Alzheimer’s disease, Nature, 375 (1995) 754–760. [22] Strittmatter, W.J., Saunders, A.M., Schmechel, D., PericakVance, M., Enghild, J., Salvensen, G.S. and Roses, A.D., Apolipoprotein E: high-avidity binding to b-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 90 (1993) 1977–1981. [23] Talbot, C., Houlden, H., Craddock, N., Crook, R., Hutton, M., Lendon, C., Prihar, G., Morris, J.C., Hardy, J. and Goate, A., Polymorphism in AACT gene may lower age of onset of Alzheimer’s disease, NeuroReport, 7 (1996) 534–536. [24] Thome, J., Baumer, A., Kornhuber, J., Rosler, R. and Riederer, P., Alpha-1-antichymotrypsin bi-allele polymorphism, apolipoprotein-E tri-allele polymorphism and genetic risk for Alzheimer’s syndrome, J. Neurol. Transm., 102 (1995) 207–212. [25] Van Broeckhoven, C., Backhovens, H., Cruts, M., Martin, J., Crook, R., Houlden, H. and Hardy, J., APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer disease, Neurosci. Lett., 169 (1994) 179–180. [26] Van Broeckhoven, C., Presenilin and Alzheimer’s disease, Nature Genet., 11 (1995) 230–232. [27] Wenham, P.R., Price, W.H. and Blundell, G., Apolipoprotein E genotyping by one stage PCR, Lancet, 337 (1991) 1158– 115928. [28] Wragg, M., Hutton, M., Talbot, C. and The Alzheimer’s disease Collaborative Group, Genetic association between intron polymorphism in presenilin-1 and late-onset Alzheimer’s disease, Lancet, 347 (1996) 509–512. [29] Yoshiiwa, A., Kamino, K., Nishiwaki, Y., Yamamoto, H., Kobayashi, T., Miki, T. and Ogihara, T., a-Antichymotrypsin gene as a risk factor for late-onset Alzheimer disease in Japanese population, Am. J. Hum. Genet., 59 (Suppl. ) (1996) A244
a-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease in the Spanish population Mario Ezquerra a, Rafael Blesa b, Eduard Tolosa b, Francisca Ballesta a, Rafael Oliva a ,* a
b
Genetic Service, Hospital Clı´nic i Provincial and University of Barcelona, Villarroel 170, Barcelona 08036, Spain Neurology Service, Hospital Clı´nic i Provincial and University of Barcelona, Villarroel 170, Barcelona 08036, Spain Received 3 November 1997; accepted 1 December 1997
Abstract The a-antichymotrypsin (ACT) and the ApoE polymorphisms have been determined in 136 Alzheimer’s disease (AD) patients and in 92 age-matched controls. Only a borderline significant difference is found when comparing the overall ACT/AA genotype frequency between AD patients and controls (x2, P = 0.08). However this difference is attributable entirely and significantly to the ApoE e4 non-carrier AD group (x2, P = 0.004). No differences are found in the ACT/AA genotype frequency of the ApoE e4 AD carrier group as compared controls (x2, P = 0.98) in contrast with previous works. These findings support that the presence of the ACT/AA genotype is a genetic risk factor for developing AD in non-ApoE e4 carriers subjects in our population. 1998 Elsevier Science Ireland Ltd.
Keywords: Alzheimer’s disease; a-Antichymotrypsin; a-Antichymotrypsin polymorphism; Genes; Apolipoprotein E; ApoE
At least four genes are clearly involved in the Alzheimer’s disease pathology at present. Mutations in the presenilin 1 gene (PS-1) [21,26], the presenilin 2 gene (PS-2) [15], and the APP gene [9] are the direct cause for some of the familial and early onset AD cases. The presence of the ApoE e4 allele increases the genetic risk for developing early and late onset AD [2,4,6,16,20,22,25]. Similarly the PS-1 1/1 intronic polymorphism has been found as a risk factor modifier for developing AD [28,7]. However the presence of the ApoE e4 allele or the presence of the PS-1 1/1 intronic polymorphism are neither necessary not sufficient to start the AD pathology. An additional candidate protein potentially involved in the biochemical process leading to the AD pathology is a-antichymotrypsin (ACT) which is a component of the senile plaques found in brains from AD patients [1,3] and binds with a high affinity to b-amyloid protein [8]. Recently it has been reported that the frequency of ACT/A allele and frequency of the ACT/AA genotype are increased in AD patients as compared to controls [12,13,17,24,29]. This correlation has not been found in * Corresponding author. Tel.: +34 3 2275510; fax: +34 3 4035260; e-mail: [email protected]
other studies [6,10,18]. In one work it has been reported that the age of onset may be lowered by the presence of the ACT/AA genotype [23]. In the present work we have evaluated the ACT polymorphism in 136 AD patients (mean age 64.4 ± 9.6) and in 92 age-matched controls (mean age 67 ± 11.8). The patients and controls came from the Hospital Clı´nic of Barcelona. The criteria for inclusion has been described in previous papers from our group [2,4,7]. The DNA was extracted from blood using the DNA direct DynabeadsTM kit. The samples were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) as previous described for ApoE and for ACT [12,27]. After polyacrylamide gel electrophoresis of the restriction enzyme digested PCR products, the bands were stained with ethidium bromide and visualised under UV light and the results recorded photographically. The results were subsequently analysed by the SSPS statistical package. We have found a higher overall ACT/AA genotype frequency in AD patients as compared to controls (41 vs. 27.7%) although at borderline significance (P = 0.08). However after stratification of the AD patients according to the ApoE status it becomes clear that the differences are attributable entirely to the ApoE e4 non-carrier group
0304-3940/98/$19.00 1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304- 3940(97) 00924- 5
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M. Ezquerra et al. / Neuroscience Letters 240 (1998) 107–109
Table 1 ACT genotypes and presence or absence of ApoE e4 alleles in Alzheimer’s patients and controls APOE e4 non-carriers (%)
ACT genotypes TT AT AA ACT alleles T A
APOE e4 carriers (%)
AD (n = 71)
Control (n = 78)
AD (n = 65)
Control (n = 14)
16.9 29.6 53.5*
19.2 52.6 28.2
21.5 50.8 27.7
21.4 50.0 28.6
30.7** 69.3
43.3 56.7
46.9 53.1
46.4 53.6
Significant differences as compared to controls: Chi-square test, *P = 0.004, **P = 0.006.
(53.5 vs. 28.2%, P = 0.004; Table 1). The ApoE e4 carrier AD group has a ACT/AA genotype frequency similar to that of the controls and it is not statistically significant (x2, P = 0.98). The odds ratio for developing AD of the ACT/ AA bearers as compared to the non-ACT/AA bearers in the non-ApoE e4 group is 2.93 (OR; 95% confidence interval (CI) = 1.529–5.64). These results are in contrast with those of Kamboh et al. [12] and Yoshiiwa et al. [29] since they found that the ACT/AA genotype is increased just in the ApoE e4 allele carrier group, but are in agreement with the results of Muramatsu et al. [17] who have found in the Japanese population the same effect described here. Some researchers do not find a genetic effect of the ACT polymorphism [6,10,18]. Thus, it is necessary to explain the heterogeneity of the results among the different populations if we assume that the ACT polymorphism really plays a role in the AD pathogenesis. The environmental and genetic factors leading to the development of AD could be different in the different populations studied and therefore the ACT polymorphism could be pathogenic only in association with other unknown genes or environmental factors. Two hypothesises are possible in explaining the effect of ApoE and ACT polymorphisms: (1) that the ACT and the ApoE genes are involved in AD pathogenesis with an additive effect; (2) that the two genes act self-sufficiently as risk factors and are competing for the pathology. Our data is consistent with the second possibility. Further evidence for the existence of two independent mechanisms is provided by the demonstration of a differential effect of the ACT and the ApoE polymorphisms on the blood cerebral flow in AD patients [11]. Alternatively, the ACT polymorphism may be in linkage disequilibrium with another mutation of this gene or another gene nearby explaining the different findings of several researchers. Recently, it has been described a possible association between the PI*M3 allele of the a1-antitrypsin (AAT) and AD [14]. The ACT and the AAT are closely related evolutionary, and encoded by two genes in close neighbourhood on chromosome 14 [5]. Genetic defects in both ACT and AAT have been found to be associated with lung and liver abnormalities [19]. This fact suggests that the two genes could also
have a common mechanism involved in AD pathology. The possibility is now open to search for these additional genetic or environment risk factors interacting or associated with the different ACT polymorphisms. Supported by a grant from the Fondo de Investigaciones FIS96/0658 to R.O. [1] Abraham, C.R., Selkoe, D.J. and Potter, H., Immunochemical identification of serine protease inhibitor a1-antitrypsin in the brain amyloid deposits of Alzheimer’s disease, Cell, 52 (1988) 487–501. [2] Adroer, R., Santacruz, P., Blesa, R., Lopez-Pousa, S., Ascaso, C. and Oliva, R., Apolipoprotein E4 allele frequency in Spanish Alzheimer and control cases, Neurosci. Lett., 189 (1995) 182– 186. [3] Bergem, A.L.M. and Lannfelt, L., Apolipoprotein E and the interaction with a1-antichymotrypsin as risk factors in Alzheimer’s disease and vascular dementia, Finding from a twin study, Neurol. Aging, 17 (Suppl. ) (1996) S61. [4] Blesa, R., Adroer, R., Santacruz, P., Ascaso, C., Tolosa, E. and Oliva, R., High apolipoprotein E allele frequency in age related memory decline, Ann. Neurol., 39 (1996) 548–552. [5] Byth, B.C., Billingsley, G.D. and Cox, D.W., Physical and genetic mapping of the serpin gene cluster at 14q32.1: allelic association and unique haplotype associated with a1-antitrypsin deficiency, Am. J. Hum. Genet., 55 (1994) 126–133. [6] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Shmechel, P.C., Gaskell, P.C., Small, G.H., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families, Science, 261 (1993) 921–923. [7] Ezquerra, M., Blesa, R., Tolosa, E., Lopez Pousa, S., Aguilar, M., Pen˜a, J., Van Broeckhoven, C., Ballesta, F. and Oliva, R., The genotype 2/2 of the presenilin-1 is decreased in Spanish early-onset Alzheimer’s disease, Neurosci. Lett., 227 (1997) 201–204. [8] Fraser, P.E., Nguyen, J.T., McLachlan, D.R., Abraham, C.R. and Kirschener, D.A., a1-antichymotrypsin binding to Alzheimer Ab peptides is sequence specific and induces fibril disagregation in vitro, J. Neurochem., 61 (1993) 298–305. [9] Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M. and Hardy, J., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease, Nature, 349 (1991) 704–709.
M. Ezquerra et al. / Neuroscience Letters 240 (1998) 107–109 [10] Haines, J.L., Pritchard, M.L., Saunders, A.M., Schildkraut, J.M., Growdon, J.H., Gaskell, P.C., Farrer, L.A., Auerbach, S.A., Gusella, J.F., Locke, P.A., Rosi, M.L., Yamaoka, L., Small, G.W., Conneally, P.M., Roses, A.D. and Pericack-Vance, M.A., No genetic effect of a1-antichymotrypsin in Alzheimer disease, Genomics, 33 (1996) 53–56. [11] Higuchi, M., Arai, H., Nakagawa, T., Higuchi, S., Muramatsu, T., Matsushita, S., Kosaka, Yi., Itho, M. and Sasaki, H., Regional cerebral glucose utilization is modulated by the dosage of apolipoprotein E type 4 allele and alpha (1) antichymotrypsin type A allele in Alzheimer’s disease, NeuroReport, 8 (12 ) (1997) 2639–2643. [12] Kamboh, M.I., Sanghera, D.K., Ferrell, R.E. and DeKosky, S.T., APOE*4 associated Alzheimer’s disease risk is modified by aantichymotrypsin polymorphism, Nature Genet., 10 (1995) 486–488. [13] Kevin, M., Morgan, L., Carpenter, K., Lowe, J., Lam, L., Cave, S., Xuereb, J., Wischik, C., Harrington, C. and Kalsheker, N.A., Microsatellite polymorphism of the a1-antichymotrypsin gene locus associated with sporadic Alzheimer’s disease, Hum. Genet., 99 (1996) 27–31. [14] Kowalska, A., Danker-Hopfe, H., Wender, M., Florczak, J. and Walter, H., Association between the PI*M3 allele of a1-antitrypsin and Alzheimer’s disease?, A preliminary report, Hum. Genet., 98 (1996) 744–746. [15] Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D.M., Oshima, J., Pettingell, W.H., Yu, C., Jondro, P.D., Schmidt, S.D., Wang, K., Crowley, A., Fu, Y., Guerelte, S., Galas, D., Nemens, E., Wijsman, E., Bird, T., Schellenberg, G. and Tanzi, R., Candidate gene for the chromosome 1 familial Alzheimer’s disease locus, Science, 269 (1995) 973–977. [16] Mayeux, R., Stern, Y., Oittman, R., Tatemichi, T.K., Tang, M.X., Maestre, G., Ngai, C., Tycko, B. and Ginsberg, H., The apolipoprotein e4 allele in patients with Alzheimer’s disease, Ann. Neurol., 34 (1993) 752–754. [17] Muramatsu, T., Matsushita, S., Arai, H., Sasaki, H. and Higuchi, S., a-Antichymotrypsin gene polymorphism and risk for Alzheimer’s disease, J. Neurol. Trans., 103 (1996) 1205–1210. [18] Nacmias, B., Tedde, A., Latorraca, S., Piacentini, S., Braco, L., Amaducci, L., Guarniere, B.M., Petrucci, C., Ortenzi, L. and Sorbi, S., Apolipoprotein E and a-antichymotrypsin gene polymorphism in Alzheimer’s disease, Ann. Neurol., 40 (1996) 678–680. [19] Poller, W., Faber, J.P., Weidinger, S., Tief, K., Scholtz, S., Fisher, M., Olek, K., Kirchgesser, M. and Heidtmann, H.H., A leucine-to-proline substitution causes a defective a-antichymotrypsinn allele associated with familial obstructive lung disease, Genomics, 17 (3 ) (1993) 740–743.
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