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Am. J. Hum. Genet.

54:643-649, 1994

Apolipoprotein E: Risk Factor for Alzheimer Disease


M.-S. Tsai,* Eric G. Tangalos,t Ronald C. Petersen,* Glenn E. Smith,5 Daniel J. Schaid,5
Emre Kokmen,* Robert J. lvnik,11 and Stephen N. Thibodeau*
*Department of Laboratory Medicine and Pathology, tDivision of Community Medicine, and Departments of tNeurology, 61Health Sciences
Research, and "Psychiatry and Psychology, Mayo Clinic, Rochester, MN

Summary
The apolipoprotein E gene (APOE) has three common alleles (2, 3, and 4) that determine six genotypes in the
general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with
an equal number of age- and sex-matched controls, for an association with the APOE-4 allele. We show that
the frequency of this allele among AD patients was significantly higher than that among the control population
(.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with
the APOE-4/3 genotype being the most common in the AD group and the APOE-3/3 being the most
common in the control group. In the AD group, homozygosity for 4 was found in nine individuals, whereas
none was found in the control group. The odds ratio for AD, when associated with one or two 4 alleles, was
4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity
for APOE-4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from
83 to 78 to 74 years as the number of APOE-4 alleles increased from 0 to 1 to 2, respectively (test for trend, P
= .001). Our data, which are in agreement with recent reports, suggest that the APOE-4 allele is associated
with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general

Tsai et al.

644

matter et al. (1993) demonstrated an association between the APOE-s4 allele and late-onset familial AD.
When combined, these data suggest a possible role for
the APOE gene, and in particular one specific isoform,
in the pathogenesis of amyloid fibril formation in AD.
In the present study, we present the association of the
most common APOE alleles and genotypes with AD
(predominately late onset) among 77 pairs of cases and
age- and sex-matched controls.
Subjects, Material, and Methods
Subjects
Patients and controls for this study were selected
from the Mayo Clinic Alzheimer's Disease Patient Registry (ADPR). The ADPR attempts to identify and
enroll all newly diagnosed cases of dementia that present to the Mayo Clinic's Division of Community Internal Medicine (DCIM). For each new dementia case
enrolled, the next age- and sex-matched, cognitively
normal person presenting to the DCIM for routine general medical evaluation is recruited as a normal control.
This sampling frame provides a community-based sample of patients that is relatively free from biases inherent
in referral populations. Controls selected from this
sampling frame are neither unusually healthy nor unhealthy but are representative of older persons seeking
routine general health care. All ADPR registrants receive a general medical examination (GME), comprehensive neurologic exam, and rigorous neuropsychologic evaluations. As part of the blood draw for GME
routine studies, an additional 15-cc sample is obtained
from those registrants consenting to provide DNA for
research purposes.
Potential dementia cases receive computed-tomography or magnetic-resonance-imaging studies and additional laboratory studies as indicated. Dementia diagnoses are based on the Diagnostic and Statistical
Manual of Mental Disorders, Third Edition, Revised
(American Psychiatric Association 1987). AD and vascular dementia diagnoses follow National Institute of
Neurological Diseases and Stroke/Alzheimer's Disease
and Related Disorders Association guidelines
(McKhann et al. 1984) and the California Alzheimer's
Disease Diagnostic and Treatment Centers criteria
(Chui et al. 1992), respectively. Diagnoses are established by consensus of the ADPR investigators, who
include a geriatrician, two behavioral neurologists, and
two neuropsychologists. Patients are followed longitudinally to death, and an autopsy is obtained for all patients from whom patient or family consent has been

obtained (-55% of all deaths). Our preliminary data


suggest that the clinical diagnoses of "probable AD" or
"control" derived by these methods are 95% concordant with subsequent autopsy neuropathological diagnoses made consistent with Khachaturian criteria (Khachaturian 1985) by our neuropathologist.
DNA Analysis

High-molecular-weight DNA was isolated from peripheral blood leukocytes (buffy coat) by using an Applied Biosystem 340A DNA Extractor (Applied Biosytems, Foster City, CA) according to the manufacturer's
instructions. DNA was amplified by utilizing a PCR
thermal cycler (Perkin Elmer Cetus) along with oligonucleotide primers APOE-A (5'-CGGGCACGGCTGTCCAAGGAG-3') and APOE-C (5'CACGCGGCCCTGTTCCACGAG-3'). Each amplification reaction
contained 250 ng of genomic DNA, 20 pmol of each
primer, 10% dimethylsulfoxide, 200 ,uM of each
dNTP, and 0.25 pJ of Taq DNA polymerase in a final
volume of 25 pl. Reaction conditions included denaturation for 30 s at 940C, annealing for 30 s at 650C, and
extension for 30 s at 720C, for 30 cycles. The PCR
products were digested with HhaI, and the fragments
were separated by electrophoresis on an 8% polyacrylamide nondenaturing gel. After electrophoresis, the gel
was treated with ethidium bromide for 30 min, and
DNA fragments were visualized by UV illumination.
APOE genotypes for the case and control groups were
determined in a blinded fashion by scoring for a unique
combination of fragment sizes, as described by Hixon
and Vernier (1990).
Statistical Method

Allele frequencies for both AD cases and controls


were estimated by counting alleles. Comparisons of genotype frequencies and allele frequencies were made
using Fisher's exact statistics. Odds ratios were estimated by maximum-likelihood estimation for matched
case-control designs, and 95% confidence intervals (CI)
were computed using exact methods (Breslow and Day
1980). Conditional logistic regression models, appropriate for our matched design, were used to assess the
contribution of APOE alleles to the odds ratio for AD.
A test for trend of age at onset of AD with the number
of APOE-s4 alleles was performed using linear regression of age (transformed using van der Waerden normal
scores to have a normal distribution) on the number of
4 alleles. Pairwise comparisons of age distributions
were performed using the Wilcoxon rank statistic.

Apo E4 in Late-Onset Alzheimer Disease

645

Table I
Comparison of APOE Genotypes and Allele Frequencies
between AD Cases and Controls
% IN
AD Groupa

Control Groupa

P-valueb

Genotype:

84/84

.........

4/3

&4/&2

.....

83/83

83/F2

2/2

11.7

40.3
6.5
35.1
6.5
0

22.1
39
57.1
15.6
1.3 J

84 .35.1
.58.4
6.5

13.0 1
76.0
11.0

.0002

Allele:
83

.00002

aN = 77.
b

P-value is calculated for all cells.

Results

At the time of these analyses, there were 554 community-based patients with cognitive impairment and their
matched controls enrolled in the ADPR. This included
382 women and 172 men. There were 135 patients with
probable or possible AD, 68 patients with probable or
possible vascular dementia, 18 with dementia from
other causes such as Parkinson disease, and 53 subjects
with mild cognitive impairment that may represent preclinical dementia (Flicker et al. 1991).
From this ADPR pool, a sample of 77 clinically probable AD patients and their age- and sex-matched controls were utilized for the present analyses. All casecontrol pairs were selected on the basis of (1) the
patient having a diagnosis of probable AD, (2) availability of a blood sample on the patient, and (3) availability
of a blood sample for the matched control. From each
group of 77, there were 57 women and 20 men, consistent with the actual gender distribution of AD in our
population (Kokmen et al. 1989). The mean age at the
time the DNA sample was obtained was 80.5 (SD = 8.9)
years for the cases and 80.0 (SD = 9.1) years for the
controls. Mean age at estimated onset of AD in the
cases was 78.7 (range 47-95) years. Six of the 77 cases
had onset at <65 years of age, and thus the study population is composed primarily of late-onset (defined as
age >65 years) AD cases. With regard to family history,
12 controls and 20 cases had at least 1 family member
(first or second degree) with dementia.

A comparison of the frequencies for the six APOE


genotypes among the case and control groups (table 1)
demonstrated a significant difference between the two
groups (P = .0002). APOE-s4/s3 was the most common genotype among the late-onset AD patients (40%),
whereas APOE-83/83 was the most common one in the

controls (57%). The three allele frequencies also differed significantly between the case and control groups
(P = .00002), with the 84 allele frequency significantly
higher among cases than among controls (.351 vs. .130,
P = .000006) (table 1). Of significance, 9 (11.7%) of the
77 cases were homozygous for the 84 allele, whereas
none of the controls were determined to be 84 homozygotes.
Table 2 compares the genotypes for paired AD and
control individuals. Compared with the control group,
the odds ratio for the association of AD with one or
two 84 alleles was 4.6 (95% CI 1.9-12.3). Although the
odds ratio for the association of AD with homozygosity
for 84 was undefined (7/0), the lower 95% confidence
limit was 1.4. On the other hand, the odds ratio for
individuals heterozygous for 84 was 3.6 (95% CI 1.5-9.8).
The association of APOE alleles with AD was also
examined separately for males and females. For males,
the APOE allele frequencies were .05 for 82, .525 for
83, and .425 for 84; for females, the frequencies were
.07, .605, and .325, respectively. These three frequencies did not differ significantly between males and females (P = .53), and, likewise, the frequency of 84 alone
also did not differ significantly between these two
groups (P = .26). Furthermore, the odds ratio for the
association of AD with one or two 84 alleles among
males (6.0) did not significantly differ from that for
females (4.0).
To further explore the relative contributions of each
of the three APOE alleles to the relative risk of AD, we
fit several conditional logistic regression models. We
Table 2
Comparison of Genotypes for Paired AD Cases and Controls
AD GENOTYPE

CONTROL GENOTYPE

84/84 ...................
4/ * ...................

*/*

.......................

Total ...................

84/84
0
2
257
9

84/ *

*/ *

TOTAL

0
11

0
7

36

32

0
20
57
77

25

NOTE.-An asterisk (*) represents 82 or 83 alleles.

Tsai et al.

646

Table 3
Logistic Model Odds Ratio Predictions
Genotype

c3/e3

e2/2
2/3

2/4
3/4
4/4
a

..........
..........

..........
..........

Model la

Model 2"

1.0
.71
.85
3.61

1.0
1.0
1.0
4.39
4.39
19.26

4.28

..........

18.30

..........

a4
log(ORij) = ai + a,;= % -.1686; a3 .0; 3and
=

b log(OR) = OX; X

no. of 4 alleles; and

1.4535.

1.4791.

defined the 83/83 genotype as the baseline risk group


for relative-risk contrasts. The first model we fit was
log (ORij) =ai + a,, where i and j present APOE alleles,
and ai (i = 2, 3, 4) is the contribution to the log odds
ratio. Because 3/3 homozygotes are the baseline
group, a3 = 0. The estimated parameters are a2
= -0.1686 and a4 = 1.4535, and the predicted odds
ratios for each of the APOE genotypes are given in table
3. This model suggests that each 84 allele contributes a
multiplicative effect of 4.3 to the genotype odds ratio.
The advantage of this model is that the odds ratio for
84/84 homozygotes can be predicted. Furthermore, we
tested interaction between alleles on the log odds ratio,
but none of the three pairwise interactions was significant. Because model 1 gives similar odds-ratio predictions for genotypes without the 84 allele (i.e., 83/83,
82/82, and 82/83) and similar odds ratios for carriers
of a single 84 allele (i.e., 82/84 and 83/84), we fit model
2, log (OR) = OX, where X is the number of 84 alleles.
The estimated parameter is 3 = 1.4791, and the predicted odds are given in table 3. These odds ratios are
similar to those given by model 1.
We next examined the relationship of age at onset
for AD and the number of 84 alleles inherited, i.e., 0, 1,
or 2 (table 4). Among the AD patients, the age at onset
tended to decrease as the number of 84 alleles increased
from 0 to 1 to 2 (test for trend, P = .001). On average,
the age at onset decreased by 4 years for each 84 allele
inherited. Pairwise comparisons by the Wilcoxon test
for age at onset resulted in P-values of .013 for 0 versus
1 84 allele, .005 for 0 versus 2 84 alleles, and .09 for 1
versus 2 84 alleles.
Discussion
The association of the apolipoprotein 84 allele has
recently been reported for both late-onset familial AD

(Corder et al. 1993; Payami et al. 1993; Strittmatter et


al. 1993) and sporadic AD (Mayeux et al. 1993; Poirier
et al. 1993; Saunders et al. 1993a, 1993b). A summary
of results from some of these studies, along with results
from our study, is shown in table 5, for comparative
purposes. Overall, our findings are in agreement with
previously published reports, in that we also find a significantly higher APOE-84 allele frequency in the AD
group (late-onset sporadic) compared with the control
group (.35 among AD versus .13 among controls). It is
interesting to note, however, that the reported apolipoprotein 84 allele frequency varies depending on the population being examined, with the sporadic cases (defined clinically) demonstrating the lowest frequency
(range 34%-38%), followed by autopsy-confirmed
cases (approximately 40%) and late-onset familial cases
(-42%-50%). There are several possible explanations
that may account for these differences. First and probably most important, current clinical criteria for the
diagnosis of AD have an inaccuracy rate, compared
with autopsy findings, of -10% (Haines 1991). Our
own unpublished observations suggest an error rate of
-5%. The actual 84 allele frequency for clinically diagnosed AD cases, therefore, would be underestimated
compared with those cases diagnosed at autopsy. Thus,
our data and those of others would suggest an 84 allele
frequency of -36% for clinically diagnosed AD cases
and -42% for autopsy diagnosed and familial AD
cases. At this point, it is unclear whether the 84 allele
frequency will be significantly increased in familial AD
compared with the other subgroups. Second, individuals with 84 alleles may be selected against because of
increased risk of atherosclerosis and coronary heart
disease (Cauley et al. 1993). Thus, the apolipoprotein s4
frequency may decrease with increasing age among the
late-onset AD cases. The mean age for the patient population in our study is one of the highest, with an obTable 4
Comparison of Doses of c4 Allele with Age at Onset
in AD Group
AGE AT ONSET
No. OF

4 ALLELES
2
1
0

...........
...........
...........

No. Median Minimum Maximum P-valuea


9
36
32

a P-value is for trend.

74.1
78.1
82.7

53.1
47.7
50.5

86.8
94.2
95.3

.001

Apo E4 in Late-Onset Alzheimer Disease

647

Table 5
Comparison of Apo-E4 Frequencies among Recent Publications
e4 FREQUENCY

(%)

STUDY
Strittmatter et al.
(1993) ..................
Saunders et al.
(1993a) .................

Poirier et al. (1993) ........


Mayeux et al. (1993) ......
Mayo Clinic ..............

Control

AD

No.

All

All

ADI

TYPE

LOAD

Familial (clinical)

(83)

50

16b

EOAD
LOAD
LOAD
LOAD
LOAD
LOAD
LOAD

Familial
Familial
Sporadic (autopsy)
Sporadic (clinical)
Sporadic (clinical)
Sporadic (clinical)
Sporadic (clinical)

(16)
(36)
(176)
(69)

19
42
40
36
38
34
35

10,c 16b

61

30

(45)
20

57

30
43

MEAN
AGE

47.2
66.1

43

12c

14

11

75.1

33

j1d
13d

10

14

80.6

a LOAD = late-onset AD; and EOAD = early-onset AD.


b CEPH.
c Spouse.
d
From the community.

served 84 allele frequency among the lowest. Third, the


APOE allele frequency is also dependent on the ethnic
and genetic background of the population being examined, and thus the control group becomes quite important. APOE allele frequencies in most Caucasian populations have been reported to be approximately
8%-12% for 82, 74%-78% for 83, and 14%-15% for 84
(Davignon et al. 1988). Although the source of the control groups in the AD studies varied considerably (individuals from the CEPH collection, normal spouse, and
individuals from the community), our data and those of
others are in general agreement, showing a range of
10%-16% for the 84 allele frequency (table 5). It is
important to note, however, that variability in the 84
allele frequency among "true and ideal" controls may
affect the variability among cases. If we assume that the
odds ratio remains relatively constant among the different populations being studied, then the 84 allele frequency should vary in a predictable manner. For example, when Hardy-Weinberg equilibrium of allele
frequencies and an odds ratio of 4.7 for one or more 84
alleles are assumed, the frequency of 84 among cases
would be expected to increase from 37% to 42%, if the
frequency among controls increased from 13% to 16%.
It is important, therefore, that appropriate controls be
utilized for such studies. Thus, the odds ratio, in addition to the 84 allele frequencies, is important and offers
further information in terms of relative risk. However,

both the odds ratio and allele frequencies can vary dramatically, as demonstrated by Mayeux et al. (1993). In
our study, the control population was derived from a
community-based patient population, and although the
control population was not specifically matched for
ethnicity, they were derived from the same community
as our cases and were matched for age and sex.
In addition to detecting a higher 4 allele frequency
among AD patients, our study confirms two other important observations that have been made, namely, the
effect of 4 allele dosage on disease susceptibility and
age at onset (Corder et al. 1993; Mayeux et al. 1993;
Poirier et al. 1993). With regard to the first of these, our
data suggest that the risk of having late-onset AD in the
general population increases with increasing dosage of
the 84 allele. We find that individuals with one or two
4 alleles are 4.6 times more likely to have late-onset
AD than those without an 84 allele. Individuals who are
heterozygous for 4 have a 3.6-fold increase in risk.
This amount of risk for heterozygotes is similar both to
that predicted by our logistic regression models and to
that observed by Mayeux et al. (1993). Because there
were no 84/84 controls, we could not directly estimate
the odds ratio for the homozygous 84/84 genotype.
However, on the basis of the logistic model, we estimate an odds ratio of 18.3 for homozygotes, which is
also similar to that estimated by Mayeux et al. (1993).
Furthermore, we estimate that the risk of AD increases

Tsai et al.

648

by a factor of -4 for each additional 4 allele, a value


similar to that reported by Mayeux et al. (1993). In
contrast, Corder et al. (1993) used the Cox proportional hazards model to estimate a relative-risk factor
of 2.84 for each additional s4 allele. Although it is not
clear why our estimates differ, several possibilities exist.
First, the AD cases we examined were sporadic (as were
cases of Mayeux et al. [1993]), whereas Corder et al.
(1993) examined familial cases and used family
members as controls. If there are genes, in addition to
APOE, that are responsible for AD in the families examined by Corder et al. (1993), then the relative risk associated with s4 may be diluted because of similar genetic
background of cases and their relatives who act as controls. Second, the risk estimates by Corder et al. (1993)
only span the ages 60-75 years, whereas ours span the
entire age range. Nonetheless, both models predict a
substantially higher risk for 4/4 homozygotes. Our
models also suggest that the effects of 2 and 3 are
similar, although the rarity of 2 alleles limits the power
of our analyses. In regard to the second observation, we
find that the dose of 4 alleles may influence the age at
onset among patients with late-onset AD. In general,
the age at onset decreased by 8 years when the number
of 4 alleles increased from 0 to 2 (test for trend, P
= .001). A similar span of a 7-year decrease was observed by Poirier et al. (1993). This decrease, however,
is less than that observed by Corder et al. (1993), who
demonstrated a 16-year difference when the number of
alleles increased from 0 to 2. Again, the differences
observed between these studies may be attributed to
the populations being studied. Our cases and those of
Poirier et al. (1993) were composed primarily of lateonset sporadic AD, while those from Corder et al.
(1993) were composed primarily of familial lateonset AD.
Overall, these data further support the role of Apo E
as an important risk factor for AD. A pathologic hallmark of AD is abnormal aggregation of insoluble 0amyloid peptide in senile plaques and cerebral vessels
(Hilbich et al. 1991). Recently, Busciglio et al. (1993)
reported that P-amyloid is generated in the secretory
pathway of amyloid precursor protein (APP) and suggested that astrocytes are a major source of P-amyloid
production in the brain. In addition, Wisniewski et al.
(1993) suggested that Apo E and other amyloid-related
proteins (e.g., amyloid p component, a1-antichymotrypsin, and glycosaminoglycan) may bind to the soluble P-amyloid and trigger a reaction with hydrophobic
parts of P-amyloid, which converts it into an insoluble
neurotoxic form resulting in amyloid fibril formation.

The strong association of the APOE-s4 allele with


late-onset AD, along with recent biochemical studies
implicating the importance of the Apo E protein in
amyloid fibril aggregation, strongly suggests the involvement of the Apo E4 isoform in the central event of
amyloid formation or in the pathogenesis of AD. Although AD is likely to be the result of multiple genetic
abnormalities, most of which are currently undefined,
our data and those of others suggest that the APOE-s4
allele may be an important risk factor for susceptibility.
Thus, APOE genotyping could be an important tool for
identifying individuals with increased risk for developing AD.
As the role of Apo E apolipoprotein is being investigated in AD, it will also be important to explore its
involvement in other forms of dementia. For example,
we are currently exploring possible associations of
APOE genotypes with patients with probable or possible vascular dementia, dementia from other causes such
as Parkinson disease, and individuals with mild cognitive impairment that may represent preclinical dementia. All of these subjects have been ascertained as part of
the Mayo Clinic ADPR.

Acknowledgments
We thank Karen Erwin for her excellent secretarial support. This project was supported in part by National Institute
on Aging grants AG 08031 and AG 06786.

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