Membership in high-risk genetic

groups predicts Alzheimers

disease and age-at-onset

Elizabeth Corder Duke University

Shirley Poduslo 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 T G C C T G G C A 3

APOE 2 Asp Val Cys Gly Arg Gln Lys Cys Leu Ala C
112 158

Apo E3 G A C G T G T G C G G C C G C C A G A A G C G C C T G G C A 3
APOE 3 Asp Val Cys Gly Arg Gln Lys Arg Leu Ala C
112 158

Apo E4 G A C G T G C G C G G C C G C C A G A A G C G C C T G G C A 3
APOE 4 Asp Val Arg Gly Arg Gln Lys Arg Leu Ala C
112 158

APOE genotypes: APOE 2 / 2 APOE 3 / 2

APOE 3 / 3 APOE 4 / 2
APOE 4 / 4 APOE 4 / 3
 APOE 4 is a susceptibility gene for AD

Science 1993

234 individuals 60 - 94 years of age:

APOE 4 Percent Risk Age at onset

with AD
APOE
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. Probabilities representing GoM groups I
to V.*

Attribute I II III IV V H

AD case 100 100 100 0 0 0.68

Age (years)
< 65 31 17 12 0 0 0.90
65- 69 30 0 0 0
70 0 45 41 41 0
75 0 0 36 59 0
80+ 0 0 0 0 100
 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 H I II III IV V H

APOE LDLr8

23 40 0 4 0 48 1.17 GG 100 100 100 99 0 0.40

33 0 0 0 100 24 AG 0 0 0 0 100

24 47 7 0 0 0 AA 0 0 0 1 0

34 0 0 96 0 28
44 19 93 0 0 0 LDLr13
TT 0 100 0 0 0 0.82

APOE 491 TC 0 0 100 53 100

AA 0 100 100 100 0 0.90 CC 100 0 0 47 0

AT 0 0 0 0 100
TT 100 0 0 0 0 CST3
GG 0 90 84 100 69 0.52

APOE-427 GA 100 0 0 0 0

TT 0 100 99 100 74 0.30 AA 0 10 16 0 31

TC 100 0 0 0 25
CC 0 0 1 0 1 CTSD
CC 0 100 100 100 100 0.41

APOCI CT 100 0 0 0 0

AA n/a 100 0 0 0 0.91

AB n/a 0 100 0 100
BB n/a 0 0 100 0
 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 high-
risk groups (I+II+III)

AD Membership

0-20% 20-40% 40-60% 60-80% 80-100%

YES (n=180) 0(0%) 11(31%) 43(61%) 24(57%) 102(100%)

NO (n=120) 50(100%) 24(69%) 28(39%) 18(43%) 0(0%)

50 35 71 42 102
 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)