- Email: [email protected]
Apolipoprotein E polymorphism in italian early onset familial and sporadic Alzheimer's disease
S132
FOURTH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE
Leiden, The Netherlands, Neurogenetics Lab, Born Bunge Foundation, Dept of Biochemistry, University of Antwerp, Belgium and Innogenetics, Gent, Belgium.
Several studies have reported an association of the apolipoprotein E allele ~4 (APOE*4) to familial and sporadic late-onset Alzheimer’s disease (LOAD). Studies of familial AD have not yielded significant evidence for a relationship between APOE* and the risk of early-onset AD (EOAD). We have studied the frequency of the APOE* allele in a Dutch population-based study of 175 EOAD patients and 159 controls. The focus of the study was on effect modification of the association between EOAD and APOE* by family history of dementia. The study comprised 198 patients diagnosed with EOAD (onset between 34 and 65 years) in the period 1980-1987 living in two areas of The Netherlands. All cases met the NINCDS-ADRDA criteria for probable AD. Age and sex matched controls were drawn randomly from the population register of the municipality of the patient. Blood samples for APOE typing were collected for 175 (89%) patients and 159 (80%) controls. The frequency of the APOEY allele in EOAD patients was 35% and 2.3 times higher than the APOE* allele frequency of 15% in controls. Among patients, the allele frequency was significantly higher in those with a positive family history (41%) than in those with a negative family history (25%). The risk of EOAD was 3.0 times [95% confidence interval 1.9-4.71 increased for carriers of at least one APOE* allele as compared to subjects without an APOE* allele. A significant increase in risk of EOAD was found for subjects homozygous for APOE* in those with a positive [OR 7.9; 1.7-36.01 and those with a negative family history of dementia [OR 4.9; l.Z-19.91. An increase in risk for APOE* heterozygotes could only be shown in subjects with a positive family history [OR 2.6; 1.2-5.71, but not in those with a negative family history [OR 1.6; 0.8-3.21 Our study shows that there is a significant association between APOE* and EOAD and that this association is modified by family history of dementia. Further, our study suggests that APOE* homozygosity is sufficient by itself to increase the risk of EOAD, while in the case of APOE* heterozygosity interaction with other genetic factors may he necessary.
genotypes in more than 125 randomly ascertained cases of probable AD who are participating in an international genetic epidemiological study called MIRAGE. The frequency of .?4 is significantly elevated @ < .OOl) in AD subjects when compared to control subjects. The results also indicate that the association between AD and ~4 is present in early-onset subjects and in cases having a high probability for a genetic disease. Analysis of parental age at birth by ApoE genotype revealed that homozygotes for c3 had fathers who were on average 3.4 years younger than fathers of subjects with other APOE genotypes. This difference is significant (P < .03). A similar trend was observed for maternal age, but the difference was smaller and not significant. Maternal and paternal ages among subjects with and without ~4 were also not significant. Further analysis revealed that the parental age effect is strongest among likely genetic cases. In this group, homozygotes for ~3 had fathers who were 8.1 years younger on average than fathers of cases with other genotypes (P = .Ol). The 5.6 year mean difference in maternal ages was also significant (P = .05). These differences were not associated with age at onset. Parental age did not differ by APOE genotype among non-genetic cases. Evaluation of parental ages in a much larger sample of AD cases and in controls grouped by APOE genotype is in progress to discern whether risk of AD is enhanced among persons having both the ~4 isoform and older fathers, or among ~3 homozygotes who have younger fathers. The latter explanation would be consistent with our previous finding of increased risk of late onsct AD among children of younger fathers. A mechanism for AD involving parental age may also explain why individuals who lack E4 can still getAD.
545 APOLIPOPROTEIN SET FAMILIAL
543 APOE IN CLINICALLY DIAGNOSED ALZHBlMBR’S DISEASE, FRONTAL LOBE DEGENERATION AND NONDBMBNTED CONTROLS C. Czech, H. F6rstl*, U. MiTnniag, S. Kreger, P. J. Tienari. Colin Masters0 and Konrad Beyteuther. Center for Molecular Biology Heidelberg, Im Neuenheimer Feld 282.69120 Heidelberg. *Central Institute of Mental Health, Department of Psychiatry, JS. 68159 Matmheim. #Department of Pathology, University of Melbourne, Parkville Victoria 3052, Australia Recent work has shown an increased frequency of the apolipoprotein E4 allele in patients with Alzheimer’s disease (AD). We have studied 42 patients satisfying NINCDS-ADRDA criteria for probable and possible AD, 7 patients with frontal lobe degeneration and 42 age-mat&d non-demented controls in order to examine the influence of diagnosis, gender and age of onset on the allele distribution. Patients and controls underwent extensive clinical examination including quantitative electroencephalography and cranial computed tomography. ApoE genotyping was performed by DNA amplification and restiction digest with CfoI, resulting fragments were resolved by 4% Metaphor (FMC) agarose gels. The frequency of ApoE was signifatly imxased in AD patients compared with the control sample. We also found a suggestive inereax of the ApoB4 allele (although not reaching statistical significance, p=O.18) in the 7 additional patients with frontal lobe degeneration, of whom two were hetemzygotes and one homozygote for ApoE4. The allele frequencies of ApoB4, in controls, in AD patients and in patients with frontal lobe degeneration were 12%. 35% and 28%. ‘Ihere was an approximately 3-fold and 7fold increased relative tisk for AD in ApoB4 betemzygotes and homozygotes, respectively. We are continuing to genotype additional control, AD and other dementia cases for these analyses.
E POLYMORPHISM
IN
ITALIAN
EARLY ON-
AND SPORADIC ALZHEIMER'S DISEASE. B.Nacmias, S.Latorraca, L. Magnelli, M.Falcini, L.Bracco, S.Piacentini, L.Amaducci and S.Sorbi. Department of Neurological Sciences, University of Florence, Florence, Italy Molecular studies of familial Alzheimer's disease (AD) have evidenced genetic heterogeneity between early onset, late onset and sporadic Alzheimer's disease. Previous studies have suggested linkage of familial AD to chromosomes 14, 19 and 21. Recently an increased frequency of apolipoprotein E ~4 allele has been described in late onset (age > 60) familial and sporadic AD (Struttmatter et al., 1993). We analized the segregation of the APOE polymorphism in 10 early onset (age at onset defined as the onset of first cognitive pedigrees, and in patients changes, < 60) italian with sporadic Alzheimer's disease. Some of the early onset AD families analized have been linked to APP (CH 21) (Sorb1 et al., 1993) or CH 14 (St George Hyslop et al., 1992 ). Our data confirm a significant association between ~4 allele and sporadic AD. In AD patients s4 allele frequency was 0.4, a value comparable with most of recent studies and suggesting an increased risk of contracting sporadic AD. The frequency of ~4 allele in early onset italian familial AD patients was comparable to control values suggesting that ~4 allele does not represent a risk factor for early onset familial AD.
546 ASSOCIATION
STUDY OF APOL1POPROTE1N E AND
SPORADIC
ALZHEIMER’S DISEASE IN THE JAPANESE POPULATION. A.Yoshiiwa’. K. Kamino’, T. Miki’, K. Nagano’, Y. Nonomura’,
544 GENETIC EPIDEMIOLOGICAL STUDIES OF APOE AND ALZHEIMER DISEASE. LA. Cupples, L.A. Farrer, E.J. Foley, E. Souza. P. Locke. S.A. Auerbach, J.H. Growdon, J.L. Haines. Depts. of Epidemiology/Biostatistics and Neurology. Boston University School of Medicine; Dept. of Neurology, Massachusetts General Hospital, Boston, MA, USA. Recent studies have demonstrated an association between isoforms of apolipopmtein E (ApoE) and risk of late-onset and sporadic Alzheimer disease) AD. However, it is unclear whether this association is limited to a specific subset of cases or how other genetic and environmental factors together with ApoE influence disease risk. We have examined ApoE
T. Ogiham’. 2Dept.
l.Dept.
Geriatric
Neumpsychiatry,
in sporadic
Medical School,
Osaka Medical College, Osaka, Japan.
‘The ~4 allele of apolipopmtein factor
H. Yoneda’ T. Sakai’ and
Medicine, Osaka University
E (ApoE) was shown as a potent genetic risk
and familial Alzheimer’s diseasefAD) in the Caucasian
population. It was suggested that apoE accelerated amyloid deposition in senile plaques and cerebral vessels. Allele frequencies of ApoE, however, vaty in different populations andin different age groups
To elucidate genetic risk factor
of Alzheimer’s disease in the Japanese population, we studied allele frequency of APO E in Japanese sporadic patients with AD using PCR-RFLP.
Seventy two
FOURTH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE
Leiden, The Netherlands, Neurogenetics Lab, Born Bunge Foundation, Dept of Biochemistry, University of Antwerp, Belgium and Innogenetics, Gent, Belgium.
Several studies have reported an association of the apolipoprotein E allele ~4 (APOE*4) to familial and sporadic late-onset Alzheimer’s disease (LOAD). Studies of familial AD have not yielded significant evidence for a relationship between APOE* and the risk of early-onset AD (EOAD). We have studied the frequency of the APOE* allele in a Dutch population-based study of 175 EOAD patients and 159 controls. The focus of the study was on effect modification of the association between EOAD and APOE* by family history of dementia. The study comprised 198 patients diagnosed with EOAD (onset between 34 and 65 years) in the period 1980-1987 living in two areas of The Netherlands. All cases met the NINCDS-ADRDA criteria for probable AD. Age and sex matched controls were drawn randomly from the population register of the municipality of the patient. Blood samples for APOE typing were collected for 175 (89%) patients and 159 (80%) controls. The frequency of the APOEY allele in EOAD patients was 35% and 2.3 times higher than the APOE* allele frequency of 15% in controls. Among patients, the allele frequency was significantly higher in those with a positive family history (41%) than in those with a negative family history (25%). The risk of EOAD was 3.0 times [95% confidence interval 1.9-4.71 increased for carriers of at least one APOE* allele as compared to subjects without an APOE* allele. A significant increase in risk of EOAD was found for subjects homozygous for APOE* in those with a positive [OR 7.9; 1.7-36.01 and those with a negative family history of dementia [OR 4.9; l.Z-19.91. An increase in risk for APOE* heterozygotes could only be shown in subjects with a positive family history [OR 2.6; 1.2-5.71, but not in those with a negative family history [OR 1.6; 0.8-3.21 Our study shows that there is a significant association between APOE* and EOAD and that this association is modified by family history of dementia. Further, our study suggests that APOE* homozygosity is sufficient by itself to increase the risk of EOAD, while in the case of APOE* heterozygosity interaction with other genetic factors may he necessary.
genotypes in more than 125 randomly ascertained cases of probable AD who are participating in an international genetic epidemiological study called MIRAGE. The frequency of .?4 is significantly elevated @ < .OOl) in AD subjects when compared to control subjects. The results also indicate that the association between AD and ~4 is present in early-onset subjects and in cases having a high probability for a genetic disease. Analysis of parental age at birth by ApoE genotype revealed that homozygotes for c3 had fathers who were on average 3.4 years younger than fathers of subjects with other APOE genotypes. This difference is significant (P < .03). A similar trend was observed for maternal age, but the difference was smaller and not significant. Maternal and paternal ages among subjects with and without ~4 were also not significant. Further analysis revealed that the parental age effect is strongest among likely genetic cases. In this group, homozygotes for ~3 had fathers who were 8.1 years younger on average than fathers of cases with other genotypes (P = .Ol). The 5.6 year mean difference in maternal ages was also significant (P = .05). These differences were not associated with age at onset. Parental age did not differ by APOE genotype among non-genetic cases. Evaluation of parental ages in a much larger sample of AD cases and in controls grouped by APOE genotype is in progress to discern whether risk of AD is enhanced among persons having both the ~4 isoform and older fathers, or among ~3 homozygotes who have younger fathers. The latter explanation would be consistent with our previous finding of increased risk of late onsct AD among children of younger fathers. A mechanism for AD involving parental age may also explain why individuals who lack E4 can still getAD.
545 APOLIPOPROTEIN SET FAMILIAL
543 APOE IN CLINICALLY DIAGNOSED ALZHBlMBR’S DISEASE, FRONTAL LOBE DEGENERATION AND NONDBMBNTED CONTROLS C. Czech, H. F6rstl*, U. MiTnniag, S. Kreger, P. J. Tienari. Colin Masters0 and Konrad Beyteuther. Center for Molecular Biology Heidelberg, Im Neuenheimer Feld 282.69120 Heidelberg. *Central Institute of Mental Health, Department of Psychiatry, JS. 68159 Matmheim. #Department of Pathology, University of Melbourne, Parkville Victoria 3052, Australia Recent work has shown an increased frequency of the apolipoprotein E4 allele in patients with Alzheimer’s disease (AD). We have studied 42 patients satisfying NINCDS-ADRDA criteria for probable and possible AD, 7 patients with frontal lobe degeneration and 42 age-mat&d non-demented controls in order to examine the influence of diagnosis, gender and age of onset on the allele distribution. Patients and controls underwent extensive clinical examination including quantitative electroencephalography and cranial computed tomography. ApoE genotyping was performed by DNA amplification and restiction digest with CfoI, resulting fragments were resolved by 4% Metaphor (FMC) agarose gels. The frequency of ApoE was signifatly imxased in AD patients compared with the control sample. We also found a suggestive inereax of the ApoB4 allele (although not reaching statistical significance, p=O.18) in the 7 additional patients with frontal lobe degeneration, of whom two were hetemzygotes and one homozygote for ApoE4. The allele frequencies of ApoB4, in controls, in AD patients and in patients with frontal lobe degeneration were 12%. 35% and 28%. ‘Ihere was an approximately 3-fold and 7fold increased relative tisk for AD in ApoB4 betemzygotes and homozygotes, respectively. We are continuing to genotype additional control, AD and other dementia cases for these analyses.
E POLYMORPHISM
IN
ITALIAN
EARLY ON-
AND SPORADIC ALZHEIMER'S DISEASE. B.Nacmias, S.Latorraca, L. Magnelli, M.Falcini, L.Bracco, S.Piacentini, L.Amaducci and S.Sorbi. Department of Neurological Sciences, University of Florence, Florence, Italy Molecular studies of familial Alzheimer's disease (AD) have evidenced genetic heterogeneity between early onset, late onset and sporadic Alzheimer's disease. Previous studies have suggested linkage of familial AD to chromosomes 14, 19 and 21. Recently an increased frequency of apolipoprotein E ~4 allele has been described in late onset (age > 60) familial and sporadic AD (Struttmatter et al., 1993). We analized the segregation of the APOE polymorphism in 10 early onset (age at onset defined as the onset of first cognitive pedigrees, and in patients changes, < 60) italian with sporadic Alzheimer's disease. Some of the early onset AD families analized have been linked to APP (CH 21) (Sorb1 et al., 1993) or CH 14 (St George Hyslop et al., 1992 ). Our data confirm a significant association between ~4 allele and sporadic AD. In AD patients s4 allele frequency was 0.4, a value comparable with most of recent studies and suggesting an increased risk of contracting sporadic AD. The frequency of ~4 allele in early onset italian familial AD patients was comparable to control values suggesting that ~4 allele does not represent a risk factor for early onset familial AD.
546 ASSOCIATION
STUDY OF APOL1POPROTE1N E AND
SPORADIC
ALZHEIMER’S DISEASE IN THE JAPANESE POPULATION. A.Yoshiiwa’. K. Kamino’, T. Miki’, K. Nagano’, Y. Nonomura’,
544 GENETIC EPIDEMIOLOGICAL STUDIES OF APOE AND ALZHEIMER DISEASE. LA. Cupples, L.A. Farrer, E.J. Foley, E. Souza. P. Locke. S.A. Auerbach, J.H. Growdon, J.L. Haines. Depts. of Epidemiology/Biostatistics and Neurology. Boston University School of Medicine; Dept. of Neurology, Massachusetts General Hospital, Boston, MA, USA. Recent studies have demonstrated an association between isoforms of apolipopmtein E (ApoE) and risk of late-onset and sporadic Alzheimer disease) AD. However, it is unclear whether this association is limited to a specific subset of cases or how other genetic and environmental factors together with ApoE influence disease risk. We have examined ApoE
T. Ogiham’. 2Dept.
l.Dept.
Geriatric
Neumpsychiatry,
in sporadic
Medical School,
Osaka Medical College, Osaka, Japan.
‘The ~4 allele of apolipopmtein factor
H. Yoneda’ T. Sakai’ and
Medicine, Osaka University
E (ApoE) was shown as a potent genetic risk
and familial Alzheimer’s diseasefAD) in the Caucasian
population. It was suggested that apoE accelerated amyloid deposition in senile plaques and cerebral vessels. Allele frequencies of ApoE, however, vaty in different populations andin different age groups
To elucidate genetic risk factor
of Alzheimer’s disease in the Japanese population, we studied allele frequency of APO E in Japanese sporadic patients with AD using PCR-RFLP.
Seventy two