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Association Between Apolipoprotein E Genotype and Alzheimer Disease in African American Subjects
Neill R. Graff-Radford, MD;
Robert C. Green, MD, MPH;
Rodney C. P. Go, PhD;
Michael L. Hutton, PhD;
Timi Edeki, MD, PhD;
David Bachman, MD;
Jennifer L. Adamson, PhD;
Patrick Griffith, MD;
Floyd B. Willis, MD;
Mary Williams, EdD, PAC;
Yvonne Hipps, PhD;
Jonathan L. Haines, PhD;
L. Adrienne Cupples, PhD;
Lindsay A. Farrer, PhD
Arch Neurol. 2002;59:594-600.
ABSTRACT
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Background The association between Alzheimer disease (AD) and genotypes at the
apolipoprotein E (APOE) locus has been confirmed
in numerous populations worldwide, but appears to be inconsistent in African
American subjects.
Objective To investigate the association between APOE
genotypes and AD in elderly African American subjects.
Design Clinic-based, multicenter case-control study and a family study.
Participants A total of 338 African American probands meeting criteria for probable
or definite AD, 301 cognitively healthy, elderly unrelated control subjects
(spouses and community volunteers), and 108 siblings of 88 AD probands.
Main Outcome Measures Odds of AD according to APOE genotype.
Results Compared with individuals with the APOE
 3/3, the odds of having AD were significantly increased
among those with 1 or more copies of the
4
allele; the odds ratio (OR) for the
3/4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the
OR for the 4/4 genotype
was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68
years of age. The risk for AD was lower among individuals with the
2/3 genotype (OR, 0.41; 95% CI, 0.22-0.79).
The patterns of association were similar in men and women. These results obtained
from comparisons of unrelated AD patients and controls were bolstered by results
of analysis of family data that showed preferential transmission of the
4 allele to demented siblings
(P<<.001)
and of the 2 allele to nondemented siblings
(P = .005).
Conclusions The presence of 1 or 2
4 alleles is a
determinant of AD risk in African American subjects. The age-related risk
for decline associated with the 4 allele and
the apparent protective effect of the 2 allele
are similar to patterns observed in white subjects.
INTRODUCTION
A GENETIC BASIS for Alzheimer disease (AD) is well established.1 Survival analysis suggests that the risk for AD is
2 to 3 times higher among first-degree relatives of patients with AD compared
with nonrelatives.2 This trend is evident in
multiple ethnic groups, including white,3-5
Hispanic,6 and African American6-7
subjects. Mutations in the amyloid precursor protein and presenilin 1 and
2 genes may be responsible for as much as 50% of familial (ie, autosomal dominant)
AD beginning before 60 years of age1, 8-10;
however, these defects have a low epidemiological impact, accounting for less
than 1% of patients worldwide.11
The genetic factor with the highest attributable risk for AD is apolipoprotein
E (APOE). The APOE gene
on chromosome 19q has 3 codominant alleles, 2, 3, and
4, differing by single-base
substitutions in the coding region of the gene. The ancestral allele,
4, is overrepresented
and 2
is underrepresented in AD.12-14
In a genetically diverse group of white subjects, the odds of AD for those
homozygous for
4 and for
3/4 heterozygotes are 14.9 and 3.2 times, respectively,
greater than the odds associated with
3 homozygosity.13 The mean age of onset of AD is 2 decades earlier
in 4 homozygotes,13-15
and the increased risk associated with the 4
allele is greater in women than in men.13-14,16-17
The APOE 4 allele
has also been found to increase AD risk in nonwhite populations, including
Chinese and Japanese.18-19
Conclusions about genetic risk for AD in African American subjects are
based on a few studies of relatively small samples. Results from community-based
samples in northern Manhattan, NY, and Indianapolis, Ind, suggest that the
association between the 4 allele and AD is
substantially weaker in African American than in white subjects.20-21
Risk for AD was not associated with APOE genotype
in a study of black Africans in Nigeria.22
A worldwide meta-analysis of the relationship between APOE and AD revealed considerable heterogeneity in the pattern of association
across individual data sets of African American subjects.13
Of the 12 data sets containing African American subjects, 10 had fewer than
30 subjects, and the others had 78 and 260. Tang and colleagues23
reported that the relative risk for AD associated with 1 or more copies of
the 4 allele was significantly increased in
white, but not in African American or Hispanic, subjects. In the absence of
the 4 allele, however, the cumulative risk
for AD to 90 years of age (adjusted for sex and education) was higher among
African American (relative risk, 4.4) than among white subjects. This latter
finding is consistent with a recent study showing that lifetime risk for AD
is higher in relatives of African American probands with AD than in relatives
of white probands, but this increased risk is not explained entirely by the 4 allele.7 In the current
study, we evaluated the APOE genotype in a large
panel of African American patients with probable AD and 2 comparison groups,
ie, siblings of the patients and ethnically matched, unrelated cognitively
normal control subjects using case-control and family-based association approaches.
SUBJECTS AND METHODS
SETTING, SUBJECTS, AND APOE GENOTYPE
A total of 252 African American AD patients meeting the criteria of
the National Institute of Neurological and Communicative Disorders and Stroke
and Alzheimer's Disease and Related Disorders Association24
for definite or probable AD were seen at 12 centers in the United States and
Canada participating in the MIRAGE [Multi-Institutional Research in Alzheimer
Genetic Epidemiology] Study. Details of the MIRAGE study design and diagnostic
protocol have been reported elsewhere.5, 25
Of these patients, 225 (89.3%) were from 3 centers in the southeastern United
States, including the University of Alabama, Birmingham; the Medical University
of South Carolina, Charleston; and Morehouse School of Medicine, Atlanta,
Ga. One hundred eleven cognitively normal spouses and elderly unrelated individuals
drawn from the same base populations as the cases were identified based on
a modified Telephone Interview Cognitive Screen score of at least 27 points.
We sought the results of the Telephone Interview Cognitive Screen and testing
of blood samples on living siblings of the AD probands. A second set of African
American subjects (86 AD patients and 190 controls) was recruited at the Mayo
Clinic in Jacksonville, Fla. All patients underwent evaluation by 1 clinician
(N.R.G.-R.) and met criteria for probable AD.24
Controls were volunteers from an elderly population being followed up longitudinally
by means of annual psychometric examinations. We used a standard polymerase
chain reaction procedure for APOE genotyping.26 Ethnicity was self-defined. All subjects were non-Hispanic.
Age and sex of the patients and unrelated controls are shown in Table 1. At the time of analysis, 88 MIRAGE patients with AD had
at least 1 sibling available for study. Characteristics of the sibships included
in the APOE analyses are shown in Table 2. Informed written consent was obtained from all subjects.
Patients underwent consecutive ascertainment, not on the basis of family history
of AD. We performed APOE genotyping after the diagnosis
was established.
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Table 1. Characteristics of Patients With AD and Unrelated Controls*
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Table 2. Characteristics of Subjects Included in Family-Based Association Tests of APOE*
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STATISTICAL METHODS
A  2 test was used to compare APOE allele frequencies between AD patients and unrelated controls. These
comparisons were repeated for subjects stratified into 3 age groups ( 70,
71-80, and  81 years). To examine the variability of the APOE-AD association across sites, we estimated an odds ratio (OR) for
AD adjusted by the data set according to the presence or absence of at least
1 4 allele using Mantel-Haenszel statistics.27 We computed the test of homogeneity of ORs of Breslow
and Day28 to assess whether data sets could
be pooled.
The influence of APOE genotype, age, and sex
on the odds of development of AD was assessed using logistic regression procedures.29 To accommodate the polychotomous classification of
APOE genotype in the regression analysis, 3 indicator variables
were constructed representing the genotype classes
2/2 or
2/3,
2/4 or
3/4, and
4/4.
These variables took on the value of 1 if the subject had the corresponding genotype, and zero otherwise.
According to this scheme, the 3/3 genotype
was considered the referent. Age of onset of AD among cases and age at last
examination among controls were assigned to an age variable. Nonlinear effects
of age were considered by means of an age-squared term. We evaluated interaction
among APOE, age, and sex by deriving product terms
for each genotype with age, age squared, and sex. Models were evaluated using
the LOGISTIC procedure in SAS version 6.12.30
Logistic modeling analyses were repeated within the 3 age groups using cutoffs
suggested by the full model before age stratification.
Sibship data were analyzed in 2 ways. In 1 approach, the odds of AD
associated with APOE genotypes in sibships, taking
into account age and sex, were computed using a logistic model with the generalized
estimating equation31 to allow for the correlation
structure among siblings. Indicator variables and interaction terms were derived
as described above. Models were estimated using the GENMOD procedure in SAS.30 Sibship data were also evaluated using the Family-Based
Association Test described by Rabinowitz and Laird32
and implemented in a computer program.33 The
Family-Based Association Test is a generalized extension of the Sibship Disequilibrium
Test, a nonparametric sign test developed for use with sibling pedigree data.34 The Sibship Disequilibrium Test examines the association
between the alleles of the marker and the trait by computing weighted probabilities
for a specific marker allele transmitted from the parents to affected and
unaffected siblings.
RESULTS
The ORs for AD associated with the 4
allele varied from 3.1 to 8.4 across sites (Table 1). However, these differences were not significantly different
(Breslow-Day test for homogeneity, P = .94). Therefore,
we conducted subsequent analyses on the pooled data.
The APOE allele and genotype distributions
were significantly different among patients and controls (Table 3), although each group is in Hardy-Weinberg equilibrium (cases, 2 = 2.0
[P = .74]; controls, 2
= 0.15 [P>.99]). The
3/4
and
4/4 genotypes confer increased
odds of AD, whereas the
2/3 genotype
is protective. Stratified analysis demonstrated a progressively smaller difference
in the frequency of the
4 allele, and
the 4/4 genotype in particular, between patients
and controls with age. In contrast, the frequency of the
3/4
genotype was substantially higher among patients compared
with controls in the youngest and oldest age cohorts, but this difference
was much smaller among subjects aged 71 to 80 years. The protective effect
of the 2/3 genotype was evident in all
age cohorts.
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Table 3. APOE Genotype and Allele Distributions
in Patients With AD and Controls by Age*
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Logistic regression analysis showed that the 2/3
genotype is protective (OR, 0.41; 95% confidence interval [CI], 0.22-0.79),
and these odds do not vary with age (Figure
1). The 4 homozygotes have significantly
increased odds (OR = 10.5; 95% CI, 5.1-21.8) of AD compared with 3 homozygotes at all ages. However, the ORs, which are remarkably
high in middle age (eg, 50 years of age, 80.6; 60 years of age, 29.5), are
greatly diminished in later years (eg, 80 years of age, 4.0; 90 years of age,
1.4). Without age stratification, the odds of AD among subjects with the
3/4
genotype are 2.6 (95% CI, 1.8-3.7). The
pattern of association between age and the
3/4
genotype on AD risk is parabolic; relative to the
3/3
genotype, the odds of AD among subjects with the
3/4
genotype is greater than 5.0 before 60 years
of age, decreases to 2.3 from 70 to 80 years of age, and steadily increases
thereafter. Although the best-fitting regression model suggests a parabolic
relationship between age and AD risk among 4
heterozygotes, the risk increase after 80 years of age is not significant.
The APOE genotype associations were not different
among men and women. We performed age-stratified logistic regression analysis
using cutoffs at 69 and 78 years suggested by the inflection points in the
curve for 4 heterozygotes from the full model
(Figure 1) to compare ORs across
age groups. Figure 2 shows that
among persons younger than 69 years, 4 heterozygosity
increased odds of AD risk 7.0 times compared with 3 homozygosity,
whereas the odds are only 1.8 and 2.6 for persons 69
to 78 years and 79 years or older, respectively. The ORs for the older groups
are marginally significantly higher than 1.0. Among persons 79 years and older,
the 3.3-fold increased odds of AD associated with 4 homozygosity are not significantly different from the baseline odds
for 3 homozygosity or from the odds for the
2/4
and 3/4 genotypes.
We also analyzed APOE genotype distributions
in 88 sibships consisting of an AD proband and at least 1 unaffected sibling.
When we assumed an additive model, results of the Family-Based Association
Test analysis showed that AD siblings were significantly more likely to have
the 4 allele (P<<.001)
and less likely to have the 2 allele (P = .005) than their unaffected siblings. Other genetic
models yielded similar results. A logistic regression analysis using the generalized
estimating equation showed that AD was more likely to develop in siblings
heterozygous or homozygous for the 4 allele
compared with siblings with the 3/3
genotype (P = .008 and P<<.001,
respectively). These results, similar to the findings from the case-control
analysis, suggest that the 3/4
and 4/4
genotypes confer an increased risk for AD among African American subjects.
COMMENT
In this multicenter study of African American patients, the odds of
AD were increased nearly 4-fold among those having at least 1 APOE
4 allele compared with subjects
with the 3/3 genotype. This elevated risk
was present in patients with 4 heterozygosity
and homozygosity, but varied substantially and generally decreased with age.
We also found that the odds of AD were 2.4 times lower among subjects with
the 2/3 genotype, again compared with
those with the 3/3 genotype. The patterns
of association were similar in men and women. These results obtained from
comparisons of samples of unrelated AD patients and controls were bolstered
from analysis of family data showing preferential transmission of the 4 allele to demented siblings and of
the 2 allele to nondemented siblings.
Previous studies of the APOE association in
community-based samples of African American subjects reported a significant
but much weaker effect of 4 homozygosity on
AD risk.20-21 There was no apparent
association with the 3/4 genotype in either
of these investigations. In contrast, the 2/3
genotype is more frequent and the 3/4
genotype is less frequent among patients in the Indianapolis study
compared with the patients in our sample (Table 4). Aside from these 2 published studies, African American
subjects have not been a focus of other investigations of the APOE-AD association. A meta-analysis13
evaluated the primary data contributed by 40 research teams, including those
of Tang and colleagues21 and a subset of the
Indianapolis cohort,35 as well as 2 other community-based
samples,36-37 and 1 clinic-based
series12 consisting of 20 to 30 African American
subjects each. The odds of carrying at least 1 4
allele among those who had AD compared with cognitively normal controls were
3.0, 3.3, and 2.0, respectively, in these smaller data sets, whereas the odds
were 0.9 in the larger data set contributed by Tang et al.13
These findings suggest that variation in the pattern of association across
studies of African American subjects are not merely due to whether the subjects
were recruited in clinic- or community-based settings.
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Table 4. APOE Genotype and Allele Distributions
in Patients With AD and Controls in Studies of African American Patients*
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The disparity in the APOE-AD association observed
in our study compared with the studies by Sahota et al20
and Tang et al21 could be due to differences
between clinic- and community-based patients, such as severity of dementia
or other concurrent illnesses. Recruitment bias of this sort might enrich
a clinic-based sample for AD cases with particular genetic mechanisms associated
with a more severe course of illness. Population stratification is an unlikely
explanation, because the APOE genotype distribution
among controls was similar across studies (Table 4). Also, different patterns of association might be related
to environmental or cultural factors. Approximately 92% of the patients in
our study were recruited from 4 cities in the southeastern United States.
Differences between the North and the South in vascular risk factors leading
to attrition of subjects from the catchment area or to modification of APOE genotype expression could account for the differences
between the current and previous studies. For example, according to the Third
National Health and Nutrition Examination Survey (1988-1991), 24% of the US
population has hypertension.38 The age-adjusted
national prevalence is higher in non-Hispanic black subjects (32.4%) overall,
and even higher for black subjects in the southeastern region of the country
(35% for black men and 37.7% for black women).39
Individuals with hypertension and the 4 allele
are more likely to die of serious coronary artery disease40-41
before AD develops. Finally, lack of an effect among subjects with the
3/4
genotype in the Indianapolis and Manhattan
samples might be due to sample size; our study included more than twice the
number of AD cases than the other 2 studies combined. However, this argument
is weakened by the observation of a significantly higher proportion of the 3/4
genotype among AD patients compared with
controls within the Birmingham and Jacksonville sites. Each of these sites
had fewer subjects than the Indianapolis or Manhattan samples (data not shown).
Differences in the association between the 4 allele and AD across studies of African American subjects may be
attributed in part to an age effect. Our results suggest that the 4 allele is a potent risk factor for AD among African American
subjects before 70 years of age, but the effect diminishes dramatically thereafter.
The AD patients in the cohort studied by Sahota et al20
were 10 years older than those in our study (mean ± SD age, 82.7 ±
6.1 vs 72.8 ± 8.6 years), and none was younger than 70 years. Most
of the AD cases in the Manhattan sample (mean ± SD age, 78 ±
7.6 years) were also older than 70 years. The odds of AD among African American
participants in our study 69 years and older with 1 or 2
4 alleles (Figure 2) are not significantly higher than the odds obtained by Sahota et al20 or Tang et al.21 Some
evidence exists of an age effect in the study by Tang et al.21
Among subjects in the youngest quartile (age, 69 years), the 4
allele frequency differed significantly (42% in AD cases and
15% in controls), which they attributed to 4 homozygotes.
Sahota et al20 also attempted to analyze the
age effect by assigning subjects to 2 age groups, using 75 years as the cutoff.
However, there were too few subjects (7 AD patients and 89 controls) younger
than 75 years to detect the age effect that we have demonstrated.
Our findings in the case-control sample of increased odds of AD among
subjects with the 3/4 and
4/4 genotypes and decreased odds among those with the
2/3 genotype are supported by the findings in
the sibships. In contrast to conventional association designs, including those
using population-based samples, the family-based approach minimizes biases
due to population stratification (ie, cases and controls not representative
of a single genetic population). The sibship design also controls for environmental
exposures, especially those shared in early life. The Sibship Disequilibrium
Test statistic evaluates the hypothesis of association, given linkage. In
other words, a significant result from this test implies that the polymorphism
under examination, or its immediate neighbor on the chromosome, is directly
related to disease susceptibility.34 Our results
suggest that AD is more likely to develop in persons who inherit the
4 allele compared with their siblings who do not.
Conversely, the inheritance of the 2 allele
confers some protection against AD.
Our results need to be interpreted with caution. We may have reached
the limits of even this comparatively large data set of African American subjects
to fit complex models. Although our sample consisted of AD patients across
the age spectrum, our sample in the group 80 years or older is less than half
the size of the samples in the other age groups. Furthermore, the AD patients
in this study may not be representative clinically or genetically of cases
in the African American community. Clinic-based patients would be expected
to have a higher genetic load (eg, higher frequency of the 4 allele) than patients recruited from the community. However, this
concern is lessened by the observation of a similar APOE-AD association among white clinic- and community-based samples.13 The use of 3 sources of unrelated controls (spouses
and age-matched individuals at the MIRAGE Study sites and community volunteers
at the Jacksonville site) is another potential source of concern. Across sites,
the controls are significantly different in sex (P
= .01), but not in age or frequency of the 4 allele.
Moreover, with respect to the APOE genotype, our
controls are similar to the controls in other community-based African American
samples (Table 4).
CONCLUSIONS
In agreement with observations from an analysis of more than 11 000
white subjects of European descent,13 the 4 allele appears to be a potent risk factor for AD, and
the 2 allele confers a protective effect against
AD in African American subjects. The association of the 4 allele is age dependent in both ethnic groups, with the major effect
of the 4 allele occurring in persons younger
than 70 years, although the patterns are not identical. A notable difference
between the 2 ethnic groups is the interaction between sex and the APOE
2/4
and 3/4
genotypes. Among white subjects, the risk for AD was
elevated in 4 heterozygotes compared
with 3 homozygotes in women only. Lack of a sex interaction
in our African American sample might be an issue of sample size or an indication
that the factors that influence sex modification in heterozygotes are not
equally frequent or do not work in the same manner in white and African American
subjects. Cross-cultural comparisons of the impact of interactions between APOE and other factors on AD susceptibility should be pursued.
AUTHOR INFORMATION
Accepted for publication December 3, 2001.
Author contributions: Study concept and design (Drs Graff-Radford, Green, Griffith, Williams, Hipps, Cupples,
and Farrer); acquisition of data (Drs Graff-Radford,
Green, Go, Hutton, Edeki, Bachman, Adamson, Willis, and Farrer); analysis
and interpretation of data (Drs Graff-Radford, Haines, Cupples,
and Farrer); drafting of the manuscript (Drs Graff-Radford,
Go, and Farrer); critical revision of the manuscript for important
intellectual content (Drs Graff-Radford, Green, Go, Hutton,
Edeki, Bachman, Adamson, Griffith, Willis, Hipps, Haines, Cupples, and Farrer); statistical expertise (Drs Haines, Cupples, and
Farrer); obtained funding (Drs Graff-Radford, Go,
Willis, and Farrer); administrative, technical, and material support (Drs Green, Go, Hutton, Edeki, Bachman, Adamson, Griffith, Willis,
Hipps, and Farrer); study supervision (Drs Go, Hutton,
Edeki, Griffith, Hipps, Haines, and Farrer).
This study was supported by grants R01-AG09029, R03-TW00866, P30-AG95004,
P50-AG16574, and P20-RR11104 from the Public Health Service via the National
Institutes of Health, Bethesda, Md, and a Merit Award from the Department
of Veterans Affairs (John Wells, PhD, and Dr Farrer), Washington, DC.
We are indebted to Jolita Dorsett, Shirley Hendrix, RN, LaShaune Lawson,
Francine Parfitt, and Nancy Sharrow, RN, for diligent efforts in data and
blood sample collection. We thank Sana Younis, Lorraine Baldwin, and Kelly
Benke for expert help in project management.
Corresponding author and reprints: Lindsay A. Farrer, PhD, Genetics
Program L-320, Boston University School of Medicine, 715 Albany St, Boston,
MA 02118 (e-mail: farrer{at}neugen.bu.edu).
From the Departments of Neurology (Dr Graff-Radford), Neuroscience
(Drs Hutton and Adamson), and Family Practice (Dr Willis), Mayo Clinic, Jacksonville,
Fla; the Genetics Program, Department of Medicine, and the Department of Neurology,
Boston University School of Medicine (Drs Green and Farrer), and the Department
of Epidemiology and Biostatistics, Boston University School of Public Health
(Drs Cupples and Farrer), Boston, Mass; the Department of Epidemiology, University
of Alabama, Birmingham (Dr Go); the Departments of Pharmacology (Dr Edeki)
and Medicine (Drs Edeki, Griffith, Williams, and Hipps), Morehouse School
of Medicine, Atlanta, Ga; the Department of Neurology, Medical University
of South Carolina, Charleston (Dr Bachman); and the Program in Human Genetics,
Vanderbilt University School of Medicine, Nashville, Tenn (Dr Haines).
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