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Apolipoprotein ϵ4 allele and disease progression in patients with late-onset Alzheimer's disease
ELSEVIER
Neuroscience Letters 183 (1995) 32-34
lmtll~
Apolipoprotein e4 allele and disease progression in patients with late-onset Alzheimer's disease H. B a s u n ~,b,*, M . G r u P ,b, B. W i n b l a d ~,b, L. L a n n f e l t ~ aKarolinska Institutet, Alzheimer Disease Research Center, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden bStockholm Gerontology Research Center, Stockholm, Sweden
Received 29 August 1994; revised version received 21 October 1994; accepted 21 October 1994
Abstract
A random sample of 60 late-onset Alzheimer's disease (AD) cases from a population-based study were apolipoprotein E (apoE) genotyped and clinically examined with a 3-year interval. The e4 allele carriers had a significantly lower age of disease onset compared to non-e4 carriers. However, no significant differences were observed between e4 allele carriers and non-carriers for Mini-Mental State Examination (MMSE) test scores at the first examination, in spite of a longer disease duration in the e4 allele carriers. After 3 years, MMSE test scores were still not significantly different between ~4 carriers and non-carriers but more than twice as many non-carriers had died. Ail other clinical features were similar between ~4 allele carriers and non-carriers. This study indicates that the e4 allele is associated with a better prognosis of the disease in late-onset AD but that there are probably factors other than the E4 allele that are important for the AD phenotype. Keywords: Alzheimer's disease; Apolipoprotein E; Disease progression; Population-based study; Clinical features
Apolipoprotein E (apoE) exists as three different isoforms coded by the e2, ~3 and e4 gene alleles. An allelic association has been demonstrated between the apoE e4 allele and late-onset familial [7,11] and sporadic AD [810]. Lack of association between the e4 allele and sporadic AD was found when using a wide criteria for familial AD, and performing extensive investigations of the family history of the patients [7]. This modification by family history of dementia was also reported by van Duijn et al., who found a higher e4 allele frequency in early-onset AD cases with a positive family history than those without [12]. In families with APP 717 and APP 670/671 mutations, individuals with the e4 allele seem to have an earlier age of disease onset compared to those without the e4 allele [6]. Furthermore, an earlier age of disease onset in e4 carriers with late-onset AD has been reported [1,7,8]. Current evidence strongly indicates a role of apoE in the pathogenesis of AD. As part of our ongoing population-based study, we have performed apoE genotyping on AD cases that were * Corresponding author, Tel.: +46 8 746 38 95; Fax: +46 8 711 17 51.
assessed for cognitive function on two occasions separated by a 3-year interval [4,5]. DNA was prepared from peripheral blood from 60 randomised AD patients by standard procedures. ApoE genotypes 2/2, 2/3, 2/4, 3/3, 3/4, and 4/4, were analysed as described previously [13]. The subjects were divided into carriers and non-carriers of the e4 allele; 205 items of demographic data including age, sex, education, marital status, place of residence, familial occurrence of dementia, age of onset of the disease (defined as the age when the first symptoms appeared), cognition, clinical symptoms and signs were analysed for possible relationships to the apoE e4 allele and the non-e4 alleles. The differences between mean values were tested with the Mann-Whitney U-test or Student's t-test (continuous variables). Category variables, such as different levels of education were tested with the X2 method. The relation between cognitive functions and apoE alleles was tested using a multiple linear regression model with MiniMental State Examination (MMSE) as the dependent variable and apoE alleles, sex, heredity, age and age of onset as the predictors [3]. The residuals were normally
0304-3940/95/$09.50 © 1995 Elsevier Science Ireland Ltd. Ail rights reserved SSDI 0304-3940(94)11107-Q
33
H. Basun et al. I Neuroscience Letters 183 (1995) 32-34
30
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GENOTYPE
Fig. 1. Apolipoprotein e genotype distribution in 60 Alzheimer disease patients randomly drawn from a population-based study.
distributed. The effect o f the e4 allele on the survival was tested in a logistic regression model with adjustment for age, age of onset, heredity o f dementia and sex. Significance levels were set at P < 0.05. Genotype frequencies are presented in Fig. 1. Twentyseven individuals of the 60 cases studied carried the e4 allele whereas 33 were non-carriers (Table 1). Disease onset was significantly lower by approximately 4 years in the e4 allele carriers .as compared to the non-carriers (Table 1). A t the time o f the first examination, the mean values of the M M S E test scores were 13.4 in e4 allele carriers as compared to 12.8 in the non-carriers (Table 1). There was no contribution to the M M S E test scores from the e4 allele when using a multiple regression model with adjustment by age, age of onset, heredity, and sex. Three years later, 25 individuals had died, two did not want to participate and one had moved from the city. M M S E mean scores had decreased at an annual rate of 2.2 points in e4 carriers and 2.0 points in non-carriers. This small difference between the groups was not statistically significant. At this time, there was still no difference in the M M S E scores between carriers and non-carriers of the e4 allele (Table 1). O f the 25 deceased, eight were e4 allele carriers and 17 non-carriers. This difference was statistically significant OE2 = 4.2; d f = 2; P = 0.04). There was no significant difference in age between the deceased e4 allele carriers and non-c~xriers. Several logistic regression models were tested. A correct prediction of 64% was found in the best modei with only genotype as independent variable. There was a contribution to mortality from the e4 allele (P = 0.07). No improvement of the model was found when age, age of onset, heredity of dementia or sex were added . Individuals in the e4 allele group were younger and had a longer duration o f disease (Table 1). Gender, education levels and whether the patient lived at home or in an institutiion were similar in both groups.
There were no differences between e4 carriers and non-carriers in other clinical variables such as blood pressure, heart rate, agnosia, apraxia, aphasia, akinesia, dyscalculia, rigidity, tremor, visuo-spatial disabilities, depressive symptoms, paranoid ideas or visual hallucinations. No symptoms of corticospinal or cerebellar dysfunction were observed in either of the groups. The corneal reflex was absent in 12 of the e4 allele carriers as compared to 3 of the non-carriers (Z2= 5.97; d f = 2 ; P = 0.05). In accordance with other studies, we found a high frequency of the e4 allele in the A D sufferers (42%) as compared to 20% in non-demented, elderly individuals from the same area in Stockholm [7]. This association of lateonset A D with the e4 allele has been confirmed in several studies, although it remains to be demonstrated if this allele is a primary cause of A D or merely a modulator of the phenotype. A more aggressive form of the disease connected with the e4 allele could be expected since e4 carriers have an earlier onset of the disease. In addition, others have shown that the brains of A D cases with the 4/4 genotype show a higher amyloid content than brains o f cases with the 3/3 genotype [9]. However, we found at the first M M S E examination that the mean test score was equal for e4 allele carriers and non-carriers, despite the fact that the e4 carriers had been iii for almost 3 years longer than the non-carriers. The mortality o f the e4 allele carriers was significantly decreased as compared to the noncarriers. This could only be explained by the genotype i n our logistic regression model and not by the difference in age or age of disease onset observed between the groups. The e4 allele seems to modify the age o f disease onset and the survival rate leading to a longer duration o f disease. An earlier age of disease onset has been associated with a longer duration of disease in A D patients [2]. A D is both genetically and clinically heterogenous. Surprisingly, we found that the A D phenotype did not differ between e4 carriers and non-carriers except for the
Table 1 Demographic and clinical data in 60 Alzheimer patients in relation to the e4 allele
N Age (mean ± SD) Male/female Age of onset Duration MMSE I MMSE 2 Deceased
Without e4 allele
With e4 allele
P
33 (55.0%) 85.8 + 6.6 6/27 81.2 ± 5.3 4.6 ± 2.8 12.8 ± 7.9 8.0 __.8.2 17
27 (45.0%) 81.6 ± 5.9 4/23 75.7 ± 5.0 6.3 + 2.9 13.4 ± 8.6 7.3 ± 7.7 8
0.02 0.73 0.001 0.04 0.74 1.00 0.04
MMSE 1, Mini-Mental State Examination test scores at the initial evaluation; MMSE 2, Mini-Mental State Examination test s c o r e s 3 years later.
34
H. Basun et al. I Neuroscience Letters 183 (1995) 32-34
age of disease onset. The absence of corneal reflex in individuals carrying the t 4 allele was considered to be of no biological sense in A D and a spurious finding due to multiple statistical testing. In summary, the e4 allele occurred at a high frequency in late-onset AD. In accordance with other studies, earlier disease onset seemed to be an effect of the 2/4, 3/4 and 4/4 genotypes, but the t 4 allele did not modify the phenotype in any other aspect. It is concluded that apoE e4 is a major risk factor o f A D [1,7], but the similarity in clinical features and cognition between t 4 carriers and noncarriers may indicate that there are other genetic or environmental factors that are important for the A D phenotype. Finally, we suggest that the e4 allele is associated with a better prognosis o f the disease in late-onset AD. The following foundations are acknowledged for supporting this study: Gamla Tjänarinnor and the Alzheimer foundation. Lena Lilius is thanked for technical assistance, Mattias Ohman for statistical advice and Dr. Richard Cowburn for valuable scientific and linguistic comments. [1] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 aUele and the risk of Alzheimer's disease in late onset farnilies, Science, 261 (1993) 921-923. [2] Duara, R., Lopez-Alberola, R.F., Barker, W.W., A comparison of familial and sporadie Alzheimer's disease, Neurology, 43 (1993) 1377-1384. [3] Folstein, M.F., Folstein, S.E., MeHugh, P.R., 'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Res., 12 (1975) 189-198. [4] Fratiglioni, L., Grut, M., Forsell, Y., Grafström, M., Holmén, K., Eriksson, K., Viitanen, M., Bäckman, L., Ahlbom, A. and Win-
[5]
[6]
[7]
[8] [9] [10]
[11]
[12]
[13]
blad, B., Prevalence of Alzheimer's disease in an elderly urban population: relationship with age, sex, and education, Neurology, 41 (1991) 1886-1892. Fratiglioni, L., Viitanen, M., Bäckman, L., Sandman, P.-O. and Winblad, B., Occurrence of dementia in advaneed age: the study design of the Kungsholmen Project, Neuroepidemiology, 11 (suppl. 1) (1992) 29-36. Hardy, J., Houlden, H., Collinge, J., Kennedy, A., Newman, S., Rossor, M., Lannfelt, L., Lilius, L., Winblad, B., Crook, R. and Duff, K., Apolipoprotein E genotype and Alzheimer's disease, Lancet, 343 (1993) 737-738. Lannfelt, L., Lilius, L., Nastase, M., Viitanen, M., Fratiglioni, L., Eggertsen, G., Berglund, L., Angelin, B., Linder, J., Winblad, B. and Basun, H., Lack of association between apolipoprotein E allele e 4 and sporadie Alzheimer's disease, Neurosei. Lett., 169 (1994) 175-178. Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P. and Gauthier, S., Apolipoprotein E polymorphism and AIzheimer's disease, Lancet, 342 (1993) 697--699. Rebeck, G.W., Reiter, J.S., Strickland, D.K. and Hyman, B.T., Apolipoprotein E in sporadic Alzheimer's disease: ailelic variation and reeeptor interactions, Neuron, 11 (1993) 575-580. Saunders, A.M., Strittmatter, W.J., Schmechel, D., St. GeorgeHyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Aibert, M.J., Hulette, C., Crain, B., Goldgaber, D., Roses, A.D., Association of apolipoprotein E allele e 4 with late-onset familial and sporadic AIzheimer's disease, Neurology, 43 (1993) 1467-1472. Strittmatter, W.J., Weisgraber, K.H., Huang, D., Dong, L.-M., Salvesen, G.S., Pericak-Vance, M., Schmeehel, D., Saunders, A.M., Goldgaber, D. and Roses, A.D., Binding of human apolipoprotein E to flA4 peptide: isoform-specific effects and imptications for late-onset Alzheimer disease, Proc. Natl. Aead. SeL USA, 90 (1993) 8098-8102. Van Duijn, C.M., de Knijff, P., Cruts, M., Wehnert, A., Havekes, L.M., Hofman, A. and Van Broeckhoven, C., Apolipoprotein FA allele in a population-based study of early onset Alzheimer's discase, Nature Genet., 7 (1994) 74-78. Wenham, P.R., Price, W.H. and Blundell, G., Apolipoprotein E genotyping by one-stage PCR, Lancet, 337 (1991) 1158-1159.
Neuroscience Letters 183 (1995) 32-34
lmtll~
Apolipoprotein e4 allele and disease progression in patients with late-onset Alzheimer's disease H. B a s u n ~,b,*, M . G r u P ,b, B. W i n b l a d ~,b, L. L a n n f e l t ~ aKarolinska Institutet, Alzheimer Disease Research Center, Department of Clinical Neuroscience and Family Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden bStockholm Gerontology Research Center, Stockholm, Sweden
Received 29 August 1994; revised version received 21 October 1994; accepted 21 October 1994
Abstract
A random sample of 60 late-onset Alzheimer's disease (AD) cases from a population-based study were apolipoprotein E (apoE) genotyped and clinically examined with a 3-year interval. The e4 allele carriers had a significantly lower age of disease onset compared to non-e4 carriers. However, no significant differences were observed between e4 allele carriers and non-carriers for Mini-Mental State Examination (MMSE) test scores at the first examination, in spite of a longer disease duration in the e4 allele carriers. After 3 years, MMSE test scores were still not significantly different between ~4 carriers and non-carriers but more than twice as many non-carriers had died. Ail other clinical features were similar between ~4 allele carriers and non-carriers. This study indicates that the e4 allele is associated with a better prognosis of the disease in late-onset AD but that there are probably factors other than the E4 allele that are important for the AD phenotype. Keywords: Alzheimer's disease; Apolipoprotein E; Disease progression; Population-based study; Clinical features
Apolipoprotein E (apoE) exists as three different isoforms coded by the e2, ~3 and e4 gene alleles. An allelic association has been demonstrated between the apoE e4 allele and late-onset familial [7,11] and sporadic AD [810]. Lack of association between the e4 allele and sporadic AD was found when using a wide criteria for familial AD, and performing extensive investigations of the family history of the patients [7]. This modification by family history of dementia was also reported by van Duijn et al., who found a higher e4 allele frequency in early-onset AD cases with a positive family history than those without [12]. In families with APP 717 and APP 670/671 mutations, individuals with the e4 allele seem to have an earlier age of disease onset compared to those without the e4 allele [6]. Furthermore, an earlier age of disease onset in e4 carriers with late-onset AD has been reported [1,7,8]. Current evidence strongly indicates a role of apoE in the pathogenesis of AD. As part of our ongoing population-based study, we have performed apoE genotyping on AD cases that were * Corresponding author, Tel.: +46 8 746 38 95; Fax: +46 8 711 17 51.
assessed for cognitive function on two occasions separated by a 3-year interval [4,5]. DNA was prepared from peripheral blood from 60 randomised AD patients by standard procedures. ApoE genotypes 2/2, 2/3, 2/4, 3/3, 3/4, and 4/4, were analysed as described previously [13]. The subjects were divided into carriers and non-carriers of the e4 allele; 205 items of demographic data including age, sex, education, marital status, place of residence, familial occurrence of dementia, age of onset of the disease (defined as the age when the first symptoms appeared), cognition, clinical symptoms and signs were analysed for possible relationships to the apoE e4 allele and the non-e4 alleles. The differences between mean values were tested with the Mann-Whitney U-test or Student's t-test (continuous variables). Category variables, such as different levels of education were tested with the X2 method. The relation between cognitive functions and apoE alleles was tested using a multiple linear regression model with MiniMental State Examination (MMSE) as the dependent variable and apoE alleles, sex, heredity, age and age of onset as the predictors [3]. The residuals were normally
0304-3940/95/$09.50 © 1995 Elsevier Science Ireland Ltd. Ail rights reserved SSDI 0304-3940(94)11107-Q
33
H. Basun et al. I Neuroscience Letters 183 (1995) 32-34
30
42% 25-
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i
i
i
i
GENOTYPE
Fig. 1. Apolipoprotein e genotype distribution in 60 Alzheimer disease patients randomly drawn from a population-based study.
distributed. The effect o f the e4 allele on the survival was tested in a logistic regression model with adjustment for age, age of onset, heredity o f dementia and sex. Significance levels were set at P < 0.05. Genotype frequencies are presented in Fig. 1. Twentyseven individuals of the 60 cases studied carried the e4 allele whereas 33 were non-carriers (Table 1). Disease onset was significantly lower by approximately 4 years in the e4 allele carriers .as compared to the non-carriers (Table 1). A t the time o f the first examination, the mean values of the M M S E test scores were 13.4 in e4 allele carriers as compared to 12.8 in the non-carriers (Table 1). There was no contribution to the M M S E test scores from the e4 allele when using a multiple regression model with adjustment by age, age of onset, heredity, and sex. Three years later, 25 individuals had died, two did not want to participate and one had moved from the city. M M S E mean scores had decreased at an annual rate of 2.2 points in e4 carriers and 2.0 points in non-carriers. This small difference between the groups was not statistically significant. At this time, there was still no difference in the M M S E scores between carriers and non-carriers of the e4 allele (Table 1). O f the 25 deceased, eight were e4 allele carriers and 17 non-carriers. This difference was statistically significant OE2 = 4.2; d f = 2; P = 0.04). There was no significant difference in age between the deceased e4 allele carriers and non-c~xriers. Several logistic regression models were tested. A correct prediction of 64% was found in the best modei with only genotype as independent variable. There was a contribution to mortality from the e4 allele (P = 0.07). No improvement of the model was found when age, age of onset, heredity of dementia or sex were added . Individuals in the e4 allele group were younger and had a longer duration o f disease (Table 1). Gender, education levels and whether the patient lived at home or in an institutiion were similar in both groups.
There were no differences between e4 carriers and non-carriers in other clinical variables such as blood pressure, heart rate, agnosia, apraxia, aphasia, akinesia, dyscalculia, rigidity, tremor, visuo-spatial disabilities, depressive symptoms, paranoid ideas or visual hallucinations. No symptoms of corticospinal or cerebellar dysfunction were observed in either of the groups. The corneal reflex was absent in 12 of the e4 allele carriers as compared to 3 of the non-carriers (Z2= 5.97; d f = 2 ; P = 0.05). In accordance with other studies, we found a high frequency of the e4 allele in the A D sufferers (42%) as compared to 20% in non-demented, elderly individuals from the same area in Stockholm [7]. This association of lateonset A D with the e4 allele has been confirmed in several studies, although it remains to be demonstrated if this allele is a primary cause of A D or merely a modulator of the phenotype. A more aggressive form of the disease connected with the e4 allele could be expected since e4 carriers have an earlier onset of the disease. In addition, others have shown that the brains of A D cases with the 4/4 genotype show a higher amyloid content than brains o f cases with the 3/3 genotype [9]. However, we found at the first M M S E examination that the mean test score was equal for e4 allele carriers and non-carriers, despite the fact that the e4 carriers had been iii for almost 3 years longer than the non-carriers. The mortality o f the e4 allele carriers was significantly decreased as compared to the noncarriers. This could only be explained by the genotype i n our logistic regression model and not by the difference in age or age of disease onset observed between the groups. The e4 allele seems to modify the age o f disease onset and the survival rate leading to a longer duration o f disease. An earlier age of disease onset has been associated with a longer duration of disease in A D patients [2]. A D is both genetically and clinically heterogenous. Surprisingly, we found that the A D phenotype did not differ between e4 carriers and non-carriers except for the
Table 1 Demographic and clinical data in 60 Alzheimer patients in relation to the e4 allele
N Age (mean ± SD) Male/female Age of onset Duration MMSE I MMSE 2 Deceased
Without e4 allele
With e4 allele
P
33 (55.0%) 85.8 + 6.6 6/27 81.2 ± 5.3 4.6 ± 2.8 12.8 ± 7.9 8.0 __.8.2 17
27 (45.0%) 81.6 ± 5.9 4/23 75.7 ± 5.0 6.3 + 2.9 13.4 ± 8.6 7.3 ± 7.7 8
0.02 0.73 0.001 0.04 0.74 1.00 0.04
MMSE 1, Mini-Mental State Examination test scores at the initial evaluation; MMSE 2, Mini-Mental State Examination test s c o r e s 3 years later.
34
H. Basun et al. I Neuroscience Letters 183 (1995) 32-34
age of disease onset. The absence of corneal reflex in individuals carrying the t 4 allele was considered to be of no biological sense in A D and a spurious finding due to multiple statistical testing. In summary, the e4 allele occurred at a high frequency in late-onset AD. In accordance with other studies, earlier disease onset seemed to be an effect of the 2/4, 3/4 and 4/4 genotypes, but the t 4 allele did not modify the phenotype in any other aspect. It is concluded that apoE e4 is a major risk factor o f A D [1,7], but the similarity in clinical features and cognition between t 4 carriers and noncarriers may indicate that there are other genetic or environmental factors that are important for the A D phenotype. Finally, we suggest that the e4 allele is associated with a better prognosis o f the disease in late-onset AD. The following foundations are acknowledged for supporting this study: Gamla Tjänarinnor and the Alzheimer foundation. Lena Lilius is thanked for technical assistance, Mattias Ohman for statistical advice and Dr. Richard Cowburn for valuable scientific and linguistic comments. [1] Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L. and Pericak-Vance, M.A., Gene dose of apolipoprotein E type 4 aUele and the risk of Alzheimer's disease in late onset farnilies, Science, 261 (1993) 921-923. [2] Duara, R., Lopez-Alberola, R.F., Barker, W.W., A comparison of familial and sporadie Alzheimer's disease, Neurology, 43 (1993) 1377-1384. [3] Folstein, M.F., Folstein, S.E., MeHugh, P.R., 'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Res., 12 (1975) 189-198. [4] Fratiglioni, L., Grut, M., Forsell, Y., Grafström, M., Holmén, K., Eriksson, K., Viitanen, M., Bäckman, L., Ahlbom, A. and Win-
[5]
[6]
[7]
[8] [9] [10]
[11]
[12]
[13]
blad, B., Prevalence of Alzheimer's disease in an elderly urban population: relationship with age, sex, and education, Neurology, 41 (1991) 1886-1892. Fratiglioni, L., Viitanen, M., Bäckman, L., Sandman, P.-O. and Winblad, B., Occurrence of dementia in advaneed age: the study design of the Kungsholmen Project, Neuroepidemiology, 11 (suppl. 1) (1992) 29-36. Hardy, J., Houlden, H., Collinge, J., Kennedy, A., Newman, S., Rossor, M., Lannfelt, L., Lilius, L., Winblad, B., Crook, R. and Duff, K., Apolipoprotein E genotype and Alzheimer's disease, Lancet, 343 (1993) 737-738. Lannfelt, L., Lilius, L., Nastase, M., Viitanen, M., Fratiglioni, L., Eggertsen, G., Berglund, L., Angelin, B., Linder, J., Winblad, B. and Basun, H., Lack of association between apolipoprotein E allele e 4 and sporadie Alzheimer's disease, Neurosei. Lett., 169 (1994) 175-178. Poirier, J., Davignon, J., Bouthillier, D., Kogan, S., Bertrand, P. and Gauthier, S., Apolipoprotein E polymorphism and AIzheimer's disease, Lancet, 342 (1993) 697--699. Rebeck, G.W., Reiter, J.S., Strickland, D.K. and Hyman, B.T., Apolipoprotein E in sporadic Alzheimer's disease: ailelic variation and reeeptor interactions, Neuron, 11 (1993) 575-580. Saunders, A.M., Strittmatter, W.J., Schmechel, D., St. GeorgeHyslop, P.H., Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., Crapper-MacLachlan, D.R., Aibert, M.J., Hulette, C., Crain, B., Goldgaber, D., Roses, A.D., Association of apolipoprotein E allele e 4 with late-onset familial and sporadic AIzheimer's disease, Neurology, 43 (1993) 1467-1472. Strittmatter, W.J., Weisgraber, K.H., Huang, D., Dong, L.-M., Salvesen, G.S., Pericak-Vance, M., Schmeehel, D., Saunders, A.M., Goldgaber, D. and Roses, A.D., Binding of human apolipoprotein E to flA4 peptide: isoform-specific effects and imptications for late-onset Alzheimer disease, Proc. Natl. Aead. SeL USA, 90 (1993) 8098-8102. Van Duijn, C.M., de Knijff, P., Cruts, M., Wehnert, A., Havekes, L.M., Hofman, A. and Van Broeckhoven, C., Apolipoprotein FA allele in a population-based study of early onset Alzheimer's discase, Nature Genet., 7 (1994) 74-78. Wenham, P.R., Price, W.H. and Blundell, G., Apolipoprotein E genotyping by one-stage PCR, Lancet, 337 (1991) 1158-1159.