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Apolipoprotein E and early-onset familial Alzheimer disease: Lack of association and age-at-onset effect
s154
FOURTHINTERNATIONALCONFERENCEONALZHEIMER'SDISEASE
GENETICS II
(where possible) one random pair consisting of one affected with ~4 and one at&ted without ~4. Mean age-at-onset for alTr&d.s with no ~4 allele was 54.1 yrs.(SE = 13.0, a = IO), younger than that of a&teds
with at least one ~4 allele: 58.7 yrs.(+ 18.9, n=IO).
We conclude that in early-oaset FAD kindreds, the presence or absence of ~4 is not associatedwith a greater risk for FAD and does iafluenee aae-atdnset. The nedierees analyzed represen~two distmct FAD loci possibly repr&ting two me&&s of
,
633
AD, in neither of which we found evidence for an ~4 effect.
Lack of association between apolipoprotein E allele e 4 and sporadic Alzbeimer’s disease. Hans Basun, Lena Lilius, Matti Viitanen, Laura Bengt Winblad, Lam Lannfelt.
Fratiglioni, Department
of Geriatric
86 Huddinge,
Medicine,
Huddinge
Karolinska
Universi@
Instituter,
Hospital,
S-141
Sweden.
Apolipoprotein E (apoE) is a protein involved in the transport of lipids and a component of Alzheimer’s disease plaques. It is abundant in the brain and this makes apoE unique among apolipoproteins. Astrocytes produce apoE, which probably
plays an important
role in nerve cell injury and
regeneration. The apoE gene is located on chromosome 19q13.2, within a region previously reported to be associated with, or linked to, late-onset familial AD. There are three common alleles of the apolipoprotein E gene, designated e 2, e 3 and e 4. An association between familial and sporadic Alzheimer’s disease and the e 4 allele was recently reported. We have investigated Swedish Alzheimer patients and controls. DNA was prepared from peripheral blood from 124 AD sufferers and 508 healthy Swedish individuals by standard procedures and apoE genotypes 2/2, 33, 2/4, 313, 3/4, and 414 were analysed. The diagnosis was made on clinical grounds (DSM III-R and NINCDS-ARDRA) and was in a few cases confirmed neuropathologically. The e 4 allele frequency in familial and sporadic cases and in control individuals was 47%. 22% and 18%, respectively. In this study, we could not confirm the previously reported association of sporadic AD with the e 4 allele, but we found an increased e 4 frequency in familial AD. The overall risk for individuals carrying
one or two copies
of the e 4
allele for developing AD was increased by a factor of 3.6, as compared with a risk of 6.2 in the familial cases. In late-onset familial AD, individuals with one or two copies of the e 4 allele were found to have an
635 THE APOLIPOPROTEIN E E4 ALLELE IS OVER-REPRESENTED IN THE LEWY BODY VARIANT OF ALZHEIMER’S DISEASE. D. Galasko, T. Saitoh, Y. Xia, R. Katzman, L.J. Thal, L. Hansen. Alz. Dis. Res. Ctr. & Dept. of Neurosciences. University of California, San Diego and Neurology Service, VA Med. Ctr. San Diego, California 92161 USA. In demented patients with Lewy Bodies (LB) and Alzheimer lesions (AD), the importance of each lesion type in producing dementia is unclear. We have called patients with LB and AD the “Lewy Body variant of AD” (LBV) because they have many clinical and pathological similarites with “pure’ AD. Because the Apolipoprotein E (ApoE) allele e4 is over-represented in lateonset AD, we studied whether ApoE allele frequencies in demented patients with LB differed from those in AD and in controls. Using DNA from frozen brain tissue from 122 autopsied demented patients, we determined ApoE genotypes by PCR, Hha I restriction enzyme digestion and polyacrylamide gel electrophoresis. ApoE e4 allele frequencies were 39.6% in AD (n=74), 29.0% in LBV (n=40), and 6.25% in diffuse Lewy Body disease without significant AD lesions (DLBD, n=6). The patient groups did not differ in mean age at death. For AD and LB, the e4 frequency was significantly higher than that reported in nondemented Caucasian controls (NC) (lo-15%) [Chi-square, pc 0.0001 overall, and p-z 0.001 for AD vs NC and LBV vs NC]. The frequencies of ApoE e4 in AD vs LBV did not differ significantly [p = 0.121. ApoE e4/e4 homozygotes were more common in AD (16%) than in LBV (5%). LBV patients had significantly lower neocortical neurofibrillary tangle counts than did AD. Therefore LBV and AD share ApoE e4 as a genetic risk factor, further evidence that these conditions overlap by virtue of their Alzheimer pathology.
earlier onset of the disease.
636 634 AFOLIPOPROTEIN OF ASSOCIATlON
E AND EARLY-ONSET FAMILIAL ALZHElMER DISEASE: LACK AND AGE-AT-ONSET EFFECT. E Levy-L.&ad, TD Bird,A I.&ad, HT
On, MBAtonsc,LL Heston,GD Schellenberg.Divisionof Neurology,University of Wash&ton, Seattle, WA 98195 USA. Late-oaset familial Alzheimer disease (FAD) and sporadic Alzheimer disease (AD) were recently shown to be associatedwith ~4, one of three alleles (~2, ~3 and ~4) of Apelipoprotein E (Apo E). This association could result from linkage disequilibrium between ApaE aad a neighboring gene which is the true susceptibility locus. Indeed, we previously found an association with a polymorphism in a nearby gene. Apalipopmtein CR. However, ~4 was reported to have a dose effect on age-at-mset in lateaasel (age > 60yrs.) FAD, which would support a fmtctioaal role for ~4 in AD. To examine whether ~4 is a biological determinant in all FAD, we analyzed its &feet on ageatattset in early.cmset FALI pedigrees (mean age at anset <60 yr.) these Pedigrees we fomtd
In
no associationbehveen c4 and FAD. This is probably due to autosomal domiaant segregation of another gene which is suflicient for expression of FAD, and is known to lx a chromosome I4 locus in most early-onset FAD kindreds ~4 is crucial in AD, it could be expeaed to be a major modifier of the disease, e.g. of age-at-onset, even in these pedigrees. We aaalyzed 2 groups of autopsydocumented early-onset FAD pedigrees: I Early-mw non-VG (ENVG): 12 muelated kindreds with strong linkage to chromosome 14q24.3 2.Volga Germans (VG): 7 families descendedfrom ethnic Germans in Russia in whom a founder effect is likely. VG are not linked to known FAD loci on chromosomes 14,21 and 19. Except for early age-at+,nset in these pedigrees is clinically and pathologically indentical to sporadic AD. Age-atanset of affeeteds was analyzed both for presencevs. absenceof s4 and for ~4 dosage (0, 1 or 2 ~4 alleles). In ENVG , mean age-at-onset of at&teds with no s4 alleles was actually younger than that of a&teds with at least one ~4 allele: 45. I years (SE = 3.7) vs. 44.1 years (SE = 5.3) In VG the mean age-at-onset was 62.2 years (SE = IO) in atTeetedswith no ~4 allele and 61.5 years (SE = 8.2) in at&teds with at least one ~4 allele t.F = 0.83). In ENVG no affect& were 64 homozygous. In VG ~4 dose did not have a signillcant effect on age-at-onset (ANOVA p = 0.95). ~4 also had no significant effti on age-at-onset using multiple regression This was true for both analvsis bv wntmlled for familv oriain (ENVG vs. VG) ~ I. oresena or
If
, AD
absenceof E4 all& &by gene dosage ofa4. Survival analysis curves for age of onset and presenceor absenceof ~4 were oxtstmcted for bath ENVG and VG. In both groups the age-at+,nset curves were not ditTerent in presenceor absenceof the ~4 allele For truly independent sampling we also selected from each family
STRUCTURAL PHENOTYPIC AND GENOTYPIC EXPRESSION OF APOLIPOPROTEIN E IN THE PRE-SENILE AND SENILE DEMENTIAS C. LVfnrd, Y. Robilnille, M. Gee, D. Tibrrghbz, L. BPririw, l? Roy, D. Gntwmtr.
D. Lnrriu&,
IMACE Project, CHCN Research Centre, Dept. of Pathology, University of Montreal, Montreal (Quebec) CANADA. An increased frequency of apolipoprotein E (apo E) ~4 allele exists in late onset Alzheimer’s disease (AD). We investigated apo E allele frequencies in sporadic AD patients, in young and elderly controls, and in five distinct groups of autopsied patients with dementia. The structural phenotypes were defined according to previously published methods (Tiberghien et al. 1993). Apo E was genotyped using a fluorescent PCR-RFLP assay in IS7 sporadic AD patients with a probable or possible clinical diagnosis, according to NINCDS-ADRDA and DSM-III criteria, and in 165 autopsied patients with dementia: 21 presenile ( 65 years) AD, 70 senile AD, 18 Lewy bodies dementia, 38 mixed AD/vascular dementia, 1R vascular dementia. The relative frequency of apo E phrwotvpr5 in the general pnpulntinn was estimated in 435 healthy donors: 20R individuals (1X-34 years old), 130 individuals (35-64 years old), and 97 individuals (65-74 years old) using an isoelectric focusing method. Controls and patients originated from the same genSraphic area: the Saguenay-Lac St Jean, Qc, Canada. The post-mortem incidence of myncardial infarction amongst 101 demented subjects who underwent a general autopsy during the first 4 years of the brain bank program was 29.7%, of which 235% were remote, and 17.6% recent. We observed Q significant association between the presence of apo E ~4 allele and specific subtypes of dementia. The ~4 allele frequencies were 0.364 in senile AD, 0.405 in presenile AD, 0.472 in Lewy bodies dementia, 0.513 in mixed AD/vascular dementia in comparison to 0.124 in elderly controls (P
FOURTHINTERNATIONALCONFERENCEONALZHEIMER'SDISEASE
GENETICS II
(where possible) one random pair consisting of one affected with ~4 and one at&ted without ~4. Mean age-at-onset for alTr&d.s with no ~4 allele was 54.1 yrs.(SE = 13.0, a = IO), younger than that of a&teds
with at least one ~4 allele: 58.7 yrs.(+ 18.9, n=IO).
We conclude that in early-oaset FAD kindreds, the presence or absence of ~4 is not associatedwith a greater risk for FAD and does iafluenee aae-atdnset. The nedierees analyzed represen~two distmct FAD loci possibly repr&ting two me&&s of
,
633
AD, in neither of which we found evidence for an ~4 effect.
Lack of association between apolipoprotein E allele e 4 and sporadic Alzbeimer’s disease. Hans Basun, Lena Lilius, Matti Viitanen, Laura Bengt Winblad, Lam Lannfelt.
Fratiglioni, Department
of Geriatric
86 Huddinge,
Medicine,
Huddinge
Karolinska
Universi@
Instituter,
Hospital,
S-141
Sweden.
Apolipoprotein E (apoE) is a protein involved in the transport of lipids and a component of Alzheimer’s disease plaques. It is abundant in the brain and this makes apoE unique among apolipoproteins. Astrocytes produce apoE, which probably
plays an important
role in nerve cell injury and
regeneration. The apoE gene is located on chromosome 19q13.2, within a region previously reported to be associated with, or linked to, late-onset familial AD. There are three common alleles of the apolipoprotein E gene, designated e 2, e 3 and e 4. An association between familial and sporadic Alzheimer’s disease and the e 4 allele was recently reported. We have investigated Swedish Alzheimer patients and controls. DNA was prepared from peripheral blood from 124 AD sufferers and 508 healthy Swedish individuals by standard procedures and apoE genotypes 2/2, 33, 2/4, 313, 3/4, and 414 were analysed. The diagnosis was made on clinical grounds (DSM III-R and NINCDS-ARDRA) and was in a few cases confirmed neuropathologically. The e 4 allele frequency in familial and sporadic cases and in control individuals was 47%. 22% and 18%, respectively. In this study, we could not confirm the previously reported association of sporadic AD with the e 4 allele, but we found an increased e 4 frequency in familial AD. The overall risk for individuals carrying
one or two copies
of the e 4
allele for developing AD was increased by a factor of 3.6, as compared with a risk of 6.2 in the familial cases. In late-onset familial AD, individuals with one or two copies of the e 4 allele were found to have an
635 THE APOLIPOPROTEIN E E4 ALLELE IS OVER-REPRESENTED IN THE LEWY BODY VARIANT OF ALZHEIMER’S DISEASE. D. Galasko, T. Saitoh, Y. Xia, R. Katzman, L.J. Thal, L. Hansen. Alz. Dis. Res. Ctr. & Dept. of Neurosciences. University of California, San Diego and Neurology Service, VA Med. Ctr. San Diego, California 92161 USA. In demented patients with Lewy Bodies (LB) and Alzheimer lesions (AD), the importance of each lesion type in producing dementia is unclear. We have called patients with LB and AD the “Lewy Body variant of AD” (LBV) because they have many clinical and pathological similarites with “pure’ AD. Because the Apolipoprotein E (ApoE) allele e4 is over-represented in lateonset AD, we studied whether ApoE allele frequencies in demented patients with LB differed from those in AD and in controls. Using DNA from frozen brain tissue from 122 autopsied demented patients, we determined ApoE genotypes by PCR, Hha I restriction enzyme digestion and polyacrylamide gel electrophoresis. ApoE e4 allele frequencies were 39.6% in AD (n=74), 29.0% in LBV (n=40), and 6.25% in diffuse Lewy Body disease without significant AD lesions (DLBD, n=6). The patient groups did not differ in mean age at death. For AD and LB, the e4 frequency was significantly higher than that reported in nondemented Caucasian controls (NC) (lo-15%) [Chi-square, pc 0.0001 overall, and p-z 0.001 for AD vs NC and LBV vs NC]. The frequencies of ApoE e4 in AD vs LBV did not differ significantly [p = 0.121. ApoE e4/e4 homozygotes were more common in AD (16%) than in LBV (5%). LBV patients had significantly lower neocortical neurofibrillary tangle counts than did AD. Therefore LBV and AD share ApoE e4 as a genetic risk factor, further evidence that these conditions overlap by virtue of their Alzheimer pathology.
earlier onset of the disease.
636 634 AFOLIPOPROTEIN OF ASSOCIATlON
E AND EARLY-ONSET FAMILIAL ALZHElMER DISEASE: LACK AND AGE-AT-ONSET EFFECT. E Levy-L.&ad, TD Bird,A I.&ad, HT
On, MBAtonsc,LL Heston,GD Schellenberg.Divisionof Neurology,University of Wash&ton, Seattle, WA 98195 USA. Late-oaset familial Alzheimer disease (FAD) and sporadic Alzheimer disease (AD) were recently shown to be associatedwith ~4, one of three alleles (~2, ~3 and ~4) of Apelipoprotein E (Apo E). This association could result from linkage disequilibrium between ApaE aad a neighboring gene which is the true susceptibility locus. Indeed, we previously found an association with a polymorphism in a nearby gene. Apalipopmtein CR. However, ~4 was reported to have a dose effect on age-at-mset in lateaasel (age > 60yrs.) FAD, which would support a fmtctioaal role for ~4 in AD. To examine whether ~4 is a biological determinant in all FAD, we analyzed its &feet on ageatattset in early.cmset FALI pedigrees (mean age at anset <60 yr.) these Pedigrees we fomtd
In
no associationbehveen c4 and FAD. This is probably due to autosomal domiaant segregation of another gene which is suflicient for expression of FAD, and is known to lx a chromosome I4 locus in most early-onset FAD kindreds ~4 is crucial in AD, it could be expeaed to be a major modifier of the disease, e.g. of age-at-onset, even in these pedigrees. We aaalyzed 2 groups of autopsydocumented early-onset FAD pedigrees: I Early-mw non-VG (ENVG): 12 muelated kindreds with strong linkage to chromosome 14q24.3 2.Volga Germans (VG): 7 families descendedfrom ethnic Germans in Russia in whom a founder effect is likely. VG are not linked to known FAD loci on chromosomes 14,21 and 19. Except for early age-at+,nset in these pedigrees is clinically and pathologically indentical to sporadic AD. Age-atanset of affeeteds was analyzed both for presencevs. absenceof s4 and for ~4 dosage (0, 1 or 2 ~4 alleles). In ENVG , mean age-at-onset of at&teds with no s4 alleles was actually younger than that of a&teds with at least one ~4 allele: 45. I years (SE = 3.7) vs. 44.1 years (SE = 5.3) In VG the mean age-at-onset was 62.2 years (SE = IO) in atTeetedswith no ~4 allele and 61.5 years (SE = 8.2) in at&teds with at least one ~4 allele t.F = 0.83). In ENVG no affect& were 64 homozygous. In VG ~4 dose did not have a signillcant effect on age-at-onset (ANOVA p = 0.95). ~4 also had no significant effti on age-at-onset using multiple regression This was true for both analvsis bv wntmlled for familv oriain (ENVG vs. VG) ~ I. oresena or
If
, AD
absenceof E4 all& &by gene dosage ofa4. Survival analysis curves for age of onset and presenceor absenceof ~4 were oxtstmcted for bath ENVG and VG. In both groups the age-at+,nset curves were not ditTerent in presenceor absenceof the ~4 allele For truly independent sampling we also selected from each family
STRUCTURAL PHENOTYPIC AND GENOTYPIC EXPRESSION OF APOLIPOPROTEIN E IN THE PRE-SENILE AND SENILE DEMENTIAS C. LVfnrd, Y. Robilnille, M. Gee, D. Tibrrghbz, L. BPririw, l? Roy, D. Gntwmtr.
D. Lnrriu&,
IMACE Project, CHCN Research Centre, Dept. of Pathology, University of Montreal, Montreal (Quebec) CANADA. An increased frequency of apolipoprotein E (apo E) ~4 allele exists in late onset Alzheimer’s disease (AD). We investigated apo E allele frequencies in sporadic AD patients, in young and elderly controls, and in five distinct groups of autopsied patients with dementia. The structural phenotypes were defined according to previously published methods (Tiberghien et al. 1993). Apo E was genotyped using a fluorescent PCR-RFLP assay in IS7 sporadic AD patients with a probable or possible clinical diagnosis, according to NINCDS-ADRDA and DSM-III criteria, and in 165 autopsied patients with dementia: 21 presenile ( 65 years) AD, 70 senile AD, 18 Lewy bodies dementia, 38 mixed AD/vascular dementia, 1R vascular dementia. The relative frequency of apo E phrwotvpr5 in the general pnpulntinn was estimated in 435 healthy donors: 20R individuals (1X-34 years old), 130 individuals (35-64 years old), and 97 individuals (65-74 years old) using an isoelectric focusing method. Controls and patients originated from the same genSraphic area: the Saguenay-Lac St Jean, Qc, Canada. The post-mortem incidence of myncardial infarction amongst 101 demented subjects who underwent a general autopsy during the first 4 years of the brain bank program was 29.7%, of which 235% were remote, and 17.6% recent. We observed Q significant association between the presence of apo E ~4 allele and specific subtypes of dementia. The ~4 allele frequencies were 0.364 in senile AD, 0.405 in presenile AD, 0.472 in Lewy bodies dementia, 0.513 in mixed AD/vascular dementia in comparison to 0.124 in elderly controls (P