Transcript Document

Membership in high-risk genetic
groups predicts Alzheimer’s
disease and age-at-onset
• Elizabeth Corder
• Shirley Poduslo
Duke University
Medical College of
Georgia
APOE is a potential susceptibility gene for AD
APOE alleles and isoforms
Apo E2
G A C
G T G
T G C
G G C
C G C
C A G
A A G
APOE 2
Asp
Val
Cys
Gly
Arg
Gln
Lys
112
G A C
G T G
T G C
G G C
C G C
C A G
A A G
APOE 3
Asp
Val
Cys
Gly
Arg
Gln
Lys
112
APOE 4
G A C
Asp
G T G
Val
C G C
Arg
112
C T G
G C A
Cys
Leu
Ala
C G C
C T G
G C A
Arg
Leu
Ala
C G C
C T G
G C A
Arg
Leu
3’
C
158
Apo E3
Apo E4
T G C
3’
C
158
G G C
Gly
C G C
Arg
C A G
Gln
A A G
Lys
158
APOE genotypes: APOE 2 / 2 APOE 3 / 2
APOE 3 / 3 APOE 4 / 2
APOE 4 / 4 APOE 4 / 3
Ala
3’
C
APOE 4 is a susceptibility gene for AD
Science 1993
234 individuals 60 - 94 years of age:
APOE 4
APOE
Percent
with AD
Risk
Age at onset
None
20 %
1.0
84 years
One
47 %
2.8
75 years
Two
91%
8.1
68 years
Background
• Some degree of AD brain changes (plaques and
tangles) is almost universal by age 80
• Extended longevity implies a strong! need to
identify root causes and interventions
• I believe that risk pertains to many genes that have
biologic plausibility but have been difficult to
verify from sample to sample due to wide
variation in frequencies of high-risk combinations
Goal
• Use GoM to define multilocus genotypes at
high and low risk for AD
• Demonstrate that persons with high
resemblance to high-risk ‘pure types’ are
affected while those with low membership
are OK
Grade of Membership analysis
(Woodbury et al., 1978)
• Lambda coefficient (): probability that a specific variable
outcome is associated with a particular pure type
• Grade of membership coefficients (gik): estimate the
degree to which a subject belongs to a pure type
Pij  gikkj
k
• Internal variables and external (validating) variables
• The number of pure types that provide the best partition of
the data matrix is determined by log likelihood tests
Data
• Age/ AD status
• APOE genotype
• Genotypes for plausible candidate loci:
–
–
–
–
–
APOE promoter polymorphisms at –491 and –427
Adjacent gene APOCI
LDL receptor for APOE
Cystatin C
Cathepsin D
Table 1.
to V.*
Probabilities representing GoM groups I
Attribute
II
III
IV
V
H
100
100
100
0
0
0.68
31
17
12
0
0
0.90
69
30
0
0
0
70
0
45
41
41
0
75
0
0
36
59
0
80+
0
0
0
0
100
AD case
I
Age (years)
< 65
65-
Group V: Long life without AD
• Permissive promotion of the APOE gene
• Several genotypes: 23, 33 and even 34!
• Heterozygosity for the LDL receptor for
APOE
Table 1.cont
I
II
III
IV
V
I
H
II
III
IV
V
H
0.40
LDLr8
APOE
GG
100
100
100
99
0
24
AG
0
0
0
0
100
0
0
AA
0
0
0
1
0
96
0
28
0
0
0
TT
0
100
0
0
0
TC
0
0
100
53
100
CC
100
0
0
47
0
GG
0
90
84
100
69
GA
100
0
0
0
0
AA
0
10
16
0
31
CC
0
100
100
100
100
CT
100
0
0
0
0
23
40
0
4
0
48
33
0
0
0
100
24
47
7
0
34
0
0
44
19
93
1.17
LDLr13
APOE –491
AA
0
100
100
100
0
AT
0
0
0
0
100
TT
100
0
0
0
0
0.90
CST3
APOE-427
TT
0
100
99
100
74
TC
100
0
0
0
25
CC
0
0
1
0
1
0.30
n/a
100
0
0
0
AB
n/a
0
100
0
100
BB
n/a
0
0
100
0
0.52
CTSD
APOCI
AA
0.82
0.91
0.41
Group I: Affected before age 70
• Ultra-high expression of APOE
• High-risk homozygous combinations of
APOE & LDL receptor genotypes
• Rare cathepsin D + cystatin C genotypes =>
that slow rate of amyloid degradation
Group II: Affected before age 75
• High-risk APOE44 in combination with an
alternate homozygous LDL exon 13
receptor genotypes, I.e. several high-risk
APOE-LDL combinations
Group III: Affected before age 80
• Common garden variety APOE34
• Unaffected group IV of similar age carried
APOE33 not APOE34
Table 2. AD status according to membership in the highrisk groups (I+II+III)
AD
Membership
0-20%
YES (n=180)
NO
(n=120)
0(0%)
20-40%
40-60%
60-80%
80-100%
11(31%)
43(61%)
24(57%) 102(100%)
50(100%) 24(69%)
28(39%)
18(43%)
50
71
42
35
0(0%)
102
Conclusions
• Identification of high-risk combinations of gene
variants jointly with the resemblance of study
subjects to the to combinations may prove to be
useful:
– To predict the level of risk and likely age at onset of AD
for individuals
– Robust verification of candidate risk genes (the
frequency of high-risk persons may vary from sample
to sample while the risk groups rooted in biology are
stable)