- Email: [email protected]
The apolipoprotein E ϵ4 allele causes a faster decline of cognitive performances in Down's syndrome subjects
JOURNAL OFTNE
N S Joumat of the Neurological Sciences 145 (1997) 87-91
The apolipoproteinE ~4 allele causes a faster decline of cognitive performancesin Down’s syndrome subjects R D
B “
G
C
bN B C A
bE C bG S
a E C b
a A D
a
a
Scientific Institute Eugenio Medea, La Nostra Famiglia, Via Don Luigi Monza 20, 22040 Bosisio Parini, Lecco, Italy b Centro Dino Ferrari, Istituto di Clinica Neurological, Uniuersita’ degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, Italy Received 2 April 1996; revised 1 July 1996; accepted 2 July 1996
A
E
apolipoprotein
i s D d p c a ( s
(
located on human chromosome
i f
r l
A
s d
d p
( e f
s
a
n
s g i
ap ●4 c s Al s
p
s d ac
h E
c t
p o
●4
i
d
b c p
f
P n p
● i
19, has three common alleles (62,
S
a
s d
a
as s
s p
a
c
p ●4
c
a
d
p
O
S
Keywords: Apolipoprotein E4; Down’s syndrome; Alzheimer’s disease; Mental retardation; Cognitive ability; Amyloid
a
I
c A
d
c
r
d d s
s c a
a
e
n f
p n
c
h
c d
d i
B
● f
N ●4
f
i
s S c
c
a a s i
S (
R A
E a
e
d (
l
a 1
p i
i e
s c
i c
g c c
a r
i t
n g
r
c
h
m i
r e
n
l h
l
ap
p c
s ‘
1 m a
* Corresponding author. Tel: +39 (31) 877111. Fax: +39 (31) 877499. 0022-510X/97/$17.00 0 1997 Ekevier Science B.V. All rights reserved. PII S0022-5 10 X(96) O0249-3
p p
ap i
i d
(
p
88
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
D e
s
ag (
c c
a
a n
c d
s d
T g
p d h
r
d
n l
i
d (
s
U
(
a p 3 e 370 N s
r a
p ●4
f u
o r
p
e
s
a y
s
a p
k
(n 02); 1 f
r
p
k t( 18 q ;2 1 q ) ; +2 + g s 5 w c
s o 1) ;
E
p
a
(
b s 6
c ( S S
e
p
a
d
S
r p
c i
l
c a
a
H
Q c v
a
s c
t A
5
I
a
t f
I
d e
p
p k r 6 t(2 1 ;2 1 ) 4
p
i
i
d
u b V
W
s 1
p e
N
s
3 a 470
f
P
p
i
p E
e
e
d
f
m
A
s a
a i
M
e s
d
O p p
5
d
g
I p a
a p
f c
a
e
p
1 X
p
n f
r (
c h
e d
m
r
g
c
a
d c
( b
a i
d
i
o
a c f m d
d
R
p d s
g f
Table 1 Comparison of the six different apoE genotypes, and of the allelic frequencies between DS patients and controls; no significant difference was determined DS patients
Controls
Genotype
All (n= 106)
M (n = 51)
F (n = 55)
AH(n = 80)
M (n = 41)
F (n = 39)
●2/c2 c2/e3 63/63 c2/e4 E3/e4 64/64
O.oi)
0.00
0.00
14,15 66.98 3.77 15.15 0.95
15.69 68.63 3.92 11.76 0.00
12.73 65.45 3.64 16.36 1,82
1.25 11,25 71.25 2.50 11.25 2.50
2,44 7.32 78.05 2.44 9,75 0.00
0.00 15.39 64,10 2.56 12.82 5.13
Allele
All (n= 212)
M (n = 102)
F (n = 110)
AH(n = 160)
M (n = 82)
F (n = 78)
E2 E3 64
8.96 81.13 9.91
9.80 82.35 7.85
8.18 80.00 11.82
8.13 82.50 9.37
7.31 86.59 6.10
8.97 78.21 12.82
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
t c
f
a
a
r
f f
A c
8
g
s
f c
e d
c
( g (
89
●4
e g
p
r
p
a
D W
A
WECHSLER
p
(
(
●4
w
D W
E I FULL
IQ
A
WECHSLER
AGE
VS
c n
a
BE~
FULL —
E I IQ
AGE
VS
–-–~
“0 ~—
I 70 60 50
30
I
04
Ei
0
5
10
1s &OE
WECHSLER
2s
20 (.d.
30
35
I
0
10
5
ars)
VERBAL
IQ
AGE
VS
UECHSLER
AGE
20
15
35
30
25
(uears)
UERBAL
IQ
VS
AGE
eO
eO ~
70 60 1
j 0
;’:-%-.%4
0
5
10
15 flGE
WECHSLER
I I
I 20
25
30
----
04 0
3s
5
10
15 AGE
(wea?s)
PER FOR M,4NCE
IQ
VS
4GE
WECHSLER
20 [uaars
25
30
35
)
PER FOR Ml+NCE
IQ
a~
VS
fiGE
“—-1 I
10 0
! 0
r: -0.567
I I I
p
10
I
r: p:
0.47
1
,~ 5
10
15
20
25
30
35
0
5
1a
15
20
25
30
35
1. Linear regression analysis of full-scale, verbal and performance intelligence quotients versus age of DS patients. Values of r (linear regression coefficient) and p are given within each diagram.
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
90
o p a
a s s
z
p
s
g
d
(
q d
●
w
p e
●
c
d
i 1
a s P
i
c
m
c
f
g
b
v
A c t
s
d n
a o r
a c p
g i
p d p n
r p
r p f
d
i
a H
s
s
s
u
a
d
d
s
c
w
9 s
●
c s
D
D
s ●4 d
A (
ap a
p
a
p
c
i d
s p a f
f
d n t
n h
m p
c
s
1
d
p
p
o
p r c
d
o (
p
a
a ac
f d p
s ●2 a e
o
r
u
u
a i
d a
b
e a s
S
e e
p A
d
c
m
c r
p i b r d c s a
o
t
a
p
c
p l
p
s
c
c c
c g
(
m c i
d
d
l d
i d
g p
s
f e
a c c
Ap b
c
d
p
c
g
c
r
t
p m p
u p l
c
d
(
f g
a
r p
as e
(
n
s
n p
d F
y
f h d
n m
q
b
a p
s
w
p d e
S
d
c
a c
b
c a
~ a s
r
s a
e
a
d
s
●4 a P=
c
y
F
●4 a c
F p
i
c
s
(
s
p
g
4
i p
s
b h m a
a
s
c F
s
s
p
p
s
f
d
m c
p
a c s
p
n t
c
o a
C g
d r
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
p e S
a
p
a
o
p
(
B e
i m p a
n
n l
d m
s
p
s
s
o
( c
c t t r p
n
i
m
m t
p s
c
i
l a c r
r a
l b
r r b
m i
i
c ●4 a
d ab
c d
af H
c
p
s A i
m t
c p
a
u g
t
r
p
R Becker, L.E., Mite, T., Takashima, S., Onodera, K., Friend, W.C. (1993) Association of phenotypic abnormalities of Down syndrome with an imbafance of genes on chromosome 21. APMIS, Suppl. 40, 101: 57-70. Carlsson, J., Armstrong, V.W., Reibert, H., Felgenhauer, K., Seidel, D. (1991) Clinical relevance of quantification of apolipoprotein E in cerebrospinal fluid. Clin. Chim. Acta, 196: 167–175. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, PC., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A. (1993) Gene dose of apolipoprotein E type 4 aflele and the risk of Alzheimer’s disease in late onset families. Science, 261: 921–923. Dickinson, M.J., Singh, I. (1993) Down’s syndrome, dementia, and superoxide dismutase. British J. Psychiatry, 162: 811–817, Han, S.-H., Einstein, G., Weisgraber, K.H., Weisgraber, K.H., Strittmatter, W.J., Saunders, A.M., Pericak-Vance, M., Roses, A.D., Schmechel, D.E.’ (1994) Apolipoprotein E is Iocafized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J. Neuropathol. Exp. Neurol., 53: 535–544. Hof, P.R., Bourns, C., Perl, D.P., Sparks, D.L., Mehta, N., Morrison, J.H. (1995) Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Arch. Nenrol., 52: 379-391. Holland, A.J., Oliver, C. (1995) Down’s syndrome and the links with Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry, 59: 111–114. Hixson J.E., Vernier D.T. (1990) Restncion isotyping of human apolipoprotein E by gene amplification by amplification and cleavage with ffhaI. J. Lipid Res. Hymrm, B.T., West, H.L., Rebeck, G.W., Lai, F., Mann, D.M.A. (1995) Neuropathological changes in Down’s syndrome hippocampal formation. Arch. Neurol., 52: 373–378. Mann, D.M.A., Yuonis, N., Jones, D., Stoddart, R.W. (1992) The time
91
course of pathological events in Down’s syndrome with particular reference to the involvement of nricroglial cells and deposits of b/A4. Neurodegeneration, 1: 201-215. Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., Ikeda, K. (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurotibrillwy tangles in Alzheimer’s disease and krrru plaque amyIoid in Creutzfeldt-Jakob disease. Brain Res., 541: 163–166. 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., l Nacmias, B., Piacentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L,, Fraser, P.E,, Rommens, J.M., St George-Hyslop, P.H. (1995) Familial . k tions in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature, 376: 775–778. Roses, A.D. (1994) Apolipoprotein E affects the rate of Alzheimer disease expression: @rnyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J. Neuropathol. Exp. Neurol., 53: 429–437. Royston, MC., Mann, D,, Pickering-Brown, S., Owen, F., Perry R., Raghavan, R., Khin-Nu, C., Tyrer, S., Day, K., Crook, R. (1994) Apolipoprotein E epsilon 2 aflele promotes longevity and protects patients with Down’s syndrome from dementia. Neuroreport, 5: 2583-2585. Saunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, St,, Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., CrapperMacLachlrm, D.R., Abcrts, M.J., Hrdette, C., Crain, B., Goldgaber, D., Roses, A.D. (1993) Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 43: 1467-1472. Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., Cmin, B.J., Hulette, C.M., Joo, S.H., Pericak-Vance, M.A., Goldgaber, D., Roses, A.D. amyloid /3-peptide deposition in cerebral cortex as a (1993) I consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA, 90: 9649–9653. Selkoe, D.J. (1994) Alzheimer’s disease: a central role for amyloid. J. Neuropathol. Exp. Neurol., 53: 438-447. Shernngton, 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., 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., St George-Hyslop, P.H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 375: 754–760. Tsai, M.-S,, Tangalos, E.G., Petersen, R.C., Smith, G.E., Schaid, D.J., Kokmen, E., Ivnik, R.J., Thibodeau, S.N. (1994) Apolipoprotein E: risk factor for Alzheimer’s disease. Am. J. Hum. Genet., 54: 643-649. Van Broeckhoven, C.L. (1995) Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur. NeuroL, 35: 8– 19. Van Gool, W.A., Evenhuis, H.M., Van Duijn, C.M. (1995) A case-control study of apolipoprotein E genotypes in Alzheimer’s disease associated with Down’s syndrome. Ann. Neurol., 38: 225–230. Weisgraber, K.H., Roses, A.D,, Strittmatter, W,J. (1994) The role of apolipoprotein E in the nervous system. Curr. Opin. Lipidol., 5: 110-116. Wenham, P.R., Price, W.H., Blundell, G. (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet, 337: 1158–1 159. Wisniewski, T., Frangione, B. (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett., 135: 235–238. Wisniewski, T., Morelli, L., Wegiel, J., Levy, E., Wisniewski, H.M., Frangione, B. (1995) The influence of apolipoprotein E isotypcs on Alzheimer’s disease pathology in 40 cases of Down’s syndrome. Ann. Neurol., 37: 136-138.
n
N S Joumat of the Neurological Sciences 145 (1997) 87-91
The apolipoproteinE ~4 allele causes a faster decline of cognitive performancesin Down’s syndrome subjects R D
B “
G
C
bN B C A
bE C bG S
a E C b
a A D
a
a
Scientific Institute Eugenio Medea, La Nostra Famiglia, Via Don Luigi Monza 20, 22040 Bosisio Parini, Lecco, Italy b Centro Dino Ferrari, Istituto di Clinica Neurological, Uniuersita’ degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, Italy Received 2 April 1996; revised 1 July 1996; accepted 2 July 1996
A
E
apolipoprotein
i s D d p c a ( s
(
located on human chromosome
i f
r l
A
s d
d p
( e f
s
a
n
s g i
ap ●4 c s Al s
p
s d ac
h E
c t
p o
●4
i
d
b c p
f
P n p
● i
19, has three common alleles (62,
S
a
s d
a
as s
s p
a
c
p ●4
c
a
d
p
O
S
Keywords: Apolipoprotein E4; Down’s syndrome; Alzheimer’s disease; Mental retardation; Cognitive ability; Amyloid
a
I
c A
d
c
r
d d s
s c a
a
e
n f
p n
c
h
c d
d i
B
● f
N ●4
f
i
s S c
c
a a s i
S (
R A
E a
e
d (
l
a 1
p i
i e
s c
i c
g c c
a r
i t
n g
r
c
h
m i
r e
n
l h
l
ap
p c
s ‘
1 m a
* Corresponding author. Tel: +39 (31) 877111. Fax: +39 (31) 877499. 0022-510X/97/$17.00 0 1997 Ekevier Science B.V. All rights reserved. PII S0022-5 10 X(96) O0249-3
p p
ap i
i d
(
p
88
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
D e
s
ag (
c c
a
a n
c d
s d
T g
p d h
r
d
n l
i
d (
s
U
(
a p 3 e 370 N s
r a
p ●4
f u
o r
p
e
s
a y
s
a p
k
(n 02); 1 f
r
p
k t( 18 q ;2 1 q ) ; +2 + g s 5 w c
s o 1) ;
E
p
a
(
b s 6
c ( S S
e
p
a
d
S
r p
c i
l
c a
a
H
Q c v
a
s c
t A
5
I
a
t f
I
d e
p
p k r 6 t(2 1 ;2 1 ) 4
p
i
i
d
u b V
W
s 1
p e
N
s
3 a 470
f
P
p
i
p E
e
e
d
f
m
A
s a
a i
M
e s
d
O p p
5
d
g
I p a
a p
f c
a
e
p
1 X
p
n f
r (
c h
e d
m
r
g
c
a
d c
( b
a i
d
i
o
a c f m d
d
R
p d s
g f
Table 1 Comparison of the six different apoE genotypes, and of the allelic frequencies between DS patients and controls; no significant difference was determined DS patients
Controls
Genotype
All (n= 106)
M (n = 51)
F (n = 55)
AH(n = 80)
M (n = 41)
F (n = 39)
●2/c2 c2/e3 63/63 c2/e4 E3/e4 64/64
O.oi)
0.00
0.00
14,15 66.98 3.77 15.15 0.95
15.69 68.63 3.92 11.76 0.00
12.73 65.45 3.64 16.36 1,82
1.25 11,25 71.25 2.50 11.25 2.50
2,44 7.32 78.05 2.44 9,75 0.00
0.00 15.39 64,10 2.56 12.82 5.13
Allele
All (n= 212)
M (n = 102)
F (n = 110)
AH(n = 160)
M (n = 82)
F (n = 78)
E2 E3 64
8.96 81.13 9.91
9.80 82.35 7.85
8.18 80.00 11.82
8.13 82.50 9.37
7.31 86.59 6.10
8.97 78.21 12.82
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
t c
f
a
a
r
f f
A c
8
g
s
f c
e d
c
( g (
89
●4
e g
p
r
p
a
D W
A
WECHSLER
p
(
(
●4
w
D W
E I FULL
IQ
A
WECHSLER
AGE
VS
c n
a
BE~
FULL —
E I IQ
AGE
VS
–-–~
“0 ~—
I 70 60 50
30
I
04
Ei
0
5
10
1s &OE
WECHSLER
2s
20 (.d.
30
35
I
0
10
5
ars)
VERBAL
IQ
AGE
VS
UECHSLER
AGE
20
15
35
30
25
(uears)
UERBAL
IQ
VS
AGE
eO
eO ~
70 60 1
j 0
;’:-%-.%4
0
5
10
15 flGE
WECHSLER
I I
I 20
25
30
----
04 0
3s
5
10
15 AGE
(wea?s)
PER FOR M,4NCE
IQ
VS
4GE
WECHSLER
20 [uaars
25
30
35
)
PER FOR Ml+NCE
IQ
a~
VS
fiGE
“—-1 I
10 0
! 0
r: -0.567
I I I
p
10
I
r: p:
0.47
1
,~ 5
10
15
20
25
30
35
0
5
1a
15
20
25
30
35
1. Linear regression analysis of full-scale, verbal and performance intelligence quotients versus age of DS patients. Values of r (linear regression coefficient) and p are given within each diagram.
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
90
o p a
a s s
z
p
s
g
d
(
q d
●
w
p e
●
c
d
i 1
a s P
i
c
m
c
f
g
b
v
A c t
s
d n
a o r
a c p
g i
p d p n
r p
r p f
d
i
a H
s
s
s
u
a
d
d
s
c
w
9 s
●
c s
D
D
s ●4 d
A (
ap a
p
a
p
c
i d
s p a f
f
d n t
n h
m p
c
s
1
d
p
p
o
p r c
d
o (
p
a
a ac
f d p
s ●2 a e
o
r
u
u
a i
d a
b
e a s
S
e e
p A
d
c
m
c r
p i b r d c s a
o
t
a
p
c
p l
p
s
c
c c
c g
(
m c i
d
d
l d
i d
g p
s
f e
a c c
Ap b
c
d
p
c
g
c
r
t
p m p
u p l
c
d
(
f g
a
r p
as e
(
n
s
n p
d F
y
f h d
n m
q
b
a p
s
w
p d e
S
d
c
a c
b
c a
~ a s
r
s a
e
a
d
s
●4 a P=
c
y
F
●4 a c
F p
i
c
s
(
s
p
g
4
i p
s
b h m a
a
s
c F
s
s
p
p
s
f
d
m c
p
a c s
p
n t
c
o a
C g
d r
R. Del Bo et al. /Journal of the Neurological Sciences 145 (1997) 87-91
p e S
a
p
a
o
p
(
B e
i m p a
n
n l
d m
s
p
s
s
o
( c
c t t r p
n
i
m
m t
p s
c
i
l a c r
r a
l b
r r b
m i
i
c ●4 a
d ab
c d
af H
c
p
s A i
m t
c p
a
u g
t
r
p
R Becker, L.E., Mite, T., Takashima, S., Onodera, K., Friend, W.C. (1993) Association of phenotypic abnormalities of Down syndrome with an imbafance of genes on chromosome 21. APMIS, Suppl. 40, 101: 57-70. Carlsson, J., Armstrong, V.W., Reibert, H., Felgenhauer, K., Seidel, D. (1991) Clinical relevance of quantification of apolipoprotein E in cerebrospinal fluid. Clin. Chim. Acta, 196: 167–175. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, PC., Small, G.W., Roses, A.D., Haines, J.L., Pericak-Vance, M.A. (1993) Gene dose of apolipoprotein E type 4 aflele and the risk of Alzheimer’s disease in late onset families. Science, 261: 921–923. Dickinson, M.J., Singh, I. (1993) Down’s syndrome, dementia, and superoxide dismutase. British J. Psychiatry, 162: 811–817, Han, S.-H., Einstein, G., Weisgraber, K.H., Weisgraber, K.H., Strittmatter, W.J., Saunders, A.M., Pericak-Vance, M., Roses, A.D., Schmechel, D.E.’ (1994) Apolipoprotein E is Iocafized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J. Neuropathol. Exp. Neurol., 53: 535–544. Hof, P.R., Bourns, C., Perl, D.P., Sparks, D.L., Mehta, N., Morrison, J.H. (1995) Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down’s syndrome. Arch. Nenrol., 52: 379-391. Holland, A.J., Oliver, C. (1995) Down’s syndrome and the links with Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry, 59: 111–114. Hixson J.E., Vernier D.T. (1990) Restncion isotyping of human apolipoprotein E by gene amplification by amplification and cleavage with ffhaI. J. Lipid Res. Hymrm, B.T., West, H.L., Rebeck, G.W., Lai, F., Mann, D.M.A. (1995) Neuropathological changes in Down’s syndrome hippocampal formation. Arch. Neurol., 52: 373–378. Mann, D.M.A., Yuonis, N., Jones, D., Stoddart, R.W. (1992) The time
91
course of pathological events in Down’s syndrome with particular reference to the involvement of nricroglial cells and deposits of b/A4. Neurodegeneration, 1: 201-215. Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., Ikeda, K. (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurotibrillwy tangles in Alzheimer’s disease and krrru plaque amyIoid in Creutzfeldt-Jakob disease. Brain Res., 541: 163–166. 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., l Nacmias, B., Piacentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L,, Fraser, P.E,, Rommens, J.M., St George-Hyslop, P.H. (1995) Familial . k tions in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature, 376: 775–778. Roses, A.D. (1994) Apolipoprotein E affects the rate of Alzheimer disease expression: @rnyloid burden is a secondary consequence dependent on APOE genotype and duration of disease. J. Neuropathol. Exp. Neurol., 53: 429–437. Royston, MC., Mann, D,, Pickering-Brown, S., Owen, F., Perry R., Raghavan, R., Khin-Nu, C., Tyrer, S., Day, K., Crook, R. (1994) Apolipoprotein E epsilon 2 aflele promotes longevity and protects patients with Down’s syndrome from dementia. Neuroreport, 5: 2583-2585. Saunders, A.M., Strittmatter, W.J., Schmechel, D., George-Hyslop, St,, Pericak-Vance, M.A., Joo, S.H., Rosi, B.L., Gusella, J.F., CrapperMacLachlrm, D.R., Abcrts, M.J., Hrdette, C., Crain, B., Goldgaber, D., Roses, A.D. (1993) Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer’s disease. Neurology, 43: 1467-1472. Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., Cmin, B.J., Hulette, C.M., Joo, S.H., Pericak-Vance, M.A., Goldgaber, D., Roses, A.D. amyloid /3-peptide deposition in cerebral cortex as a (1993) I consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl. Acad. Sci. USA, 90: 9649–9653. Selkoe, D.J. (1994) Alzheimer’s disease: a central role for amyloid. J. Neuropathol. Exp. Neurol., 53: 438-447. Shernngton, 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., 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., St George-Hyslop, P.H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 375: 754–760. Tsai, M.-S,, Tangalos, E.G., Petersen, R.C., Smith, G.E., Schaid, D.J., Kokmen, E., Ivnik, R.J., Thibodeau, S.N. (1994) Apolipoprotein E: risk factor for Alzheimer’s disease. Am. J. Hum. Genet., 54: 643-649. Van Broeckhoven, C.L. (1995) Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur. NeuroL, 35: 8– 19. Van Gool, W.A., Evenhuis, H.M., Van Duijn, C.M. (1995) A case-control study of apolipoprotein E genotypes in Alzheimer’s disease associated with Down’s syndrome. Ann. Neurol., 38: 225–230. Weisgraber, K.H., Roses, A.D,, Strittmatter, W,J. (1994) The role of apolipoprotein E in the nervous system. Curr. Opin. Lipidol., 5: 110-116. Wenham, P.R., Price, W.H., Blundell, G. (1991) Apolipoprotein E genotyping by one-stage PCR. Lancet, 337: 1158–1 159. Wisniewski, T., Frangione, B. (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett., 135: 235–238. Wisniewski, T., Morelli, L., Wegiel, J., Levy, E., Wisniewski, H.M., Frangione, B. (1995) The influence of apolipoprotein E isotypcs on Alzheimer’s disease pathology in 40 cases of Down’s syndrome. Ann. Neurol., 37: 136-138.
n