Context Evidence exists that the incidence of Alzheimer disease (AD), as well
as risk attributable to specific genetic factors such as apolipoprotein E
(APOE) genotype, may vary considerably among ethnic
groups. Family studies of probands with AD offer an opportunity to evaluate
lifetime risk of dementia among relatives of these probands.
Objective To compare lifetime dementia risk estimates among relatives of white
and African American probands with probable or definite AD.
Design and Setting Risk analysis using data collected by questionnaire and supplemental
records between May 1991 and March 2001 at 17 medical centers contributing
to the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study.
Participants A total of 17 639 first-degree biological relatives and 2474 spouses
of 2339 white AD probands, and 2281 first-degree biological relatives and
257 spouses of 255 African American AD probands.
Main Outcome Measures Cumulative risk of dementia by age 85 years, stratified by ethnicity
and sex of relatives and by APOE genotype of probands.
Results Cumulative risk of dementia in first-degree biological relatives of
African American AD probands by age 85 years was 43.7% (SE, 3.1%), and the
corresponding risk in first-degree biological relatives of white AD probands
was 26.9% (SE, 0.8%), yielding a relative risk (RR) of 1.6 (95% confidence
interval [CI], 1.4-1.9; P<.001). The risk in spouses
of African American AD probands of 18.5% (SE, 8.4%) was also higher than the
risk in white spouses of 10.4% (SE, 1.7%) but did not reach statistical significance
(RR, 1.8; 95% CI, 0.5-6.0; P = .34), likely due to
the smaller sample size of African Americans. The proportional increase in
risk of dementia among white first-degree biological relatives compared with
white spouses of 2.6 (95% CI, 2.1-3.2) was similar to that of 2.4 (95% CI,
1.3-4.4) in African American first-degree biological relatives compared with
African American spouses. Female first-degree biological relatives of probands
had a higher risk of developing dementia than did their male counterparts,
among whites (31.2% vs 20.4%; RR, 1.5; 95% CI, 1.3-1.7; P<.001) as well as among African Americans, although this was not
significant among African Americans (46.7% vs 40.1%; RR, 1.2; 95% CI, 0.9-1.7, P = .30). The patterns of risk among first-degree biological
relatives stratified by APOE genotype of the probands
were similar in white families and African American families.
Conclusion First-degree relatives of African Americans with AD have a higher cumulative
risk of dementia than do those of whites with AD. However, in this study,
the additional risk of dementia conferred by being a first-degree relative,
by being female, or by the probability of having an APOE ∊4 allele appeared similar in African American and white families.
These data provide estimates of dementia risk that can be used to offer counseling
to family members of patients with AD.
Well-established risk factors for the development of Alzheimer disease
(AD) in white populations include age, family history, female sex, and the
presence of 1 or 2 copies of the apolipoprotein E (APOE) ∊4 allele.1,2 Family
studies have shown that relatives of white AD patients are at greater risk
than nonrelatives for the development of dementia, and that these risks are
higher with increasing age, female sex, and the likelihood of carrying 1 or
2 copies of the APOE ∊4 allele.3-6
The risks associated with AD in other US ethnicities and among populations
in other countries have been less thoroughly studied, but there is evidence
that the incidence of disease, as well as the risk attributable to specific
genetic factors such as APOE genotype, may vary considerably
among ethnic groups.2,7-10
Family studies of probands with AD who have been identified by uniform
criteria offer an opportunity to evaluate the lifetime risk of dementia among
relatives of these probands. Comparisons of risk in biological relatives and
nonbiological relatives (such as spouses) can help distinguish genetic from
nongenetic factors within families. The impact of APOE
genotype on the risk of dementia among relatives can be assessed indirectly
by stratifying the lifetime risk estimates among biological relatives according
to the APOE genotype of the proband. We have collected
these types of data for 10 years within the Multi-Institutional Research in
Alzheimer's Genetic Epidemiology (MIRAGE) study, and the lifetime risk estimates
obtained in white populations have already provided clinically applicable
estimates of risk among first-degree relatives in families of white patients
with AD.1,5,6 We
have now collected family history data on the largest number of African American
families ever studied for AD, to our knowledge. In this study, we report the
lifetime risk estimates of dementia for the first-degree biological relatives
of probands with AD by ethnicity, and examine the additional risk of dementia
conferred on relatives by being female and by the probability of having an APOE ∊4 allele. Risk estimates generated by this analysis
also provide empirical data to which clinicians can refer when counseling
the relatives of their patients with AD who are concerned about their own
risk of developing AD.
Participants and Data Collection
The details of MIRAGE Study data collection procedures, protocols for
obtaining family histories, and reports demonstrating the validity of proxy
reporting in participating families have been published elsewhere.6,11,12 In brief, probands
or individuals with probable or definite AD by research criteria13
were identified at specialty clinics for dementia by experienced clinician-researchers
at 17 centers between May 1991 and March 2001. The structured and validated
MIRAGE questionnaires were distributed to family members to elicit health
information and dementia status on the entire family. Information on both
patients and family members was supplemented by multiple informants, medical
records including autopsy reports, death certificates, and nursing home records.
Informed consent was obtained from family members who did not have dementia,
and a combination of consent or assent, along with informed consent by proxy,
was obtained from participants with dementia.
Family history information was available for 2594 probands meeting criteria
for definite or probable AD. Age, sex, and dementia status information was
incorporated from 19 920 first-degree biological relatives of these probands,
as well as from 2731 of the probands' spouses. Data on other risk factors
for AD were elicited as described elsewhere.6,11,14
In a subset of 1331 family members 50 years or older who were reported by
family informants not to have dementia, cognitive status was confirmed to
be normal in 1298 (97.5%) by the modified Telephone Interview of Cognitive
Status (mTICS).15,16
Of the first-degree biological relatives, 4681 were parents of the proband
(817 affected), 8474 were siblings (715 affected), and 6765 were children
(11 affected). There were 1093 families with at least 1 affected first-degree
biological relative, indicating that about 42% of the probands had a family
history of AD. Of these 1093 families, 784 (71.7%) had 1 affected first-degree
biological relative, 216 (19.8%) had 2 affected first-degree biological relatives,
and 93 (8.5%) had more than 2 affected first-degree biological relatives.
Ethnicity of participating families was classified by self-report, then
reclassified prior to the analysis following the format of the 1990 US Census.17 This analysis was restricted to families in which
the proband met criteria for African American or white ethnicity. Age represented
the age at which dementia symptoms began in relatives with dementia, or the
age at which information was obtained on relatives who did not have dementia.
Blood for APOE genotyping was collected on a subset
of 1191 (45.9%) of the probands. A standard polymerase chain reaction procedure18 was used for APOE genotyping.
Of these samples, 458 (38.5%) were genotyped as APOE ∊2/∊2, ∊2/∊3,
or ∊3/∊3; 561 (47.1%), APOE ∊2/∊4
or ∊3/∊4; and 172 (14.4%), APOE ∊4/∊4.
The APOE genotype of the proband was grouped into
the following 3 categories: ∊2/∊2, ∊2/∊3, or ∊3/∊3; ∊2/∊4
or ∊3/∊4; and ∊4/∊4 genotypes.
A maximum likelihood procedure similar to a Kaplan-Meier survival analysis
was used to estimate the lifetime risks and age at onset distribution for
first-degree biological relatives and spouses of the AD probands.5,19 The Kaplan-Meier method takes into
account the possibility that those censored at the time of the study may be
susceptible and acquire AD after the study end point and that those who died
of a competing risk might have acquired AD if they had survived. Our method
incorporates these elements into the analysis, but we additionally incorporate
affected individuals with unknown ages of onset and nonaffected individuals
with unknown censoring ages, thereby avoiding a downward bias in the estimation
of mean onset age that would otherwise occur.19
We used maximum likelihood estimation for 5 groups of individuals: (1) affected
individuals with known age of onset, (2) unaffected individuals with known
censoring age, (3) affected individuals with unknown onset age but with known
censoring age, eg, death, (4) affected individuals without known onset age
or censoring age, and (5) unaffected individuals without any censoring information.
The expectation-maximization algorithm was applied to take into account censored
information. In our analysis, 1459 of the 19 920 first-degree biological
relatives of probands were included in the analysis that would not have been
included in the traditional Kaplan-Meier method. Asymptotically normal distributions
of maximum likelihood statistics were used to compute Z tests by using parameter estimates for risk and their SEs at the maximum
common age of 95 years for each ethnic group, and for comparison across groups
using risk by age 85 years.
Risk estimates were calculated with stratification by sex, ethnicity,
and both sex and ethnicity of the relatives and spouses. Risk estimates among
first-degree biological relatives were also stratified according to APOE genotype category of the proband.
All analyses were performed using SAS software version 8.2 (SAS Institute
Inc, Cary, NC).
Cumulative risk was estimated based on information gathered from the
families of 2339 white and 255 African American probands. The characteristics
of the probands, first-degree biological relatives, and spouses are reported
in Table 1. Cumulative risk estimates
for first-degree biological relatives, stratified by ethnicity, sex, and by
the APOE genotype of the proband, and cumulative
risk estimates for spouses stratified by ethnicity are shown in Table 2. Curves illustrating the cumulative risks at different ages
are shown in Figure 1, Figure 2, and Figure 3. As shown in Figure 1,
the cumulative risk (SE) of dementia to age 95 years among first-degree biological
relatives of white probands was 43.7% (1.9%) while the risk of dementia to
age 95 years among first-degree biological relatives of African American probands
was 57.1% (5.6%) (relative risk [RR], 1.3; 95% confidence interval [CI], 1.03-1.6; P = .02).
The results that follow refer to cumulative risks of dementia by age
85 years. The cumulative risk (SE) of dementia among first-degree biological
relatives of white probands was 26.9% (0.8%) while the risk of dementia among
first-degree biological relatives of African American probands was 43.7% (3.1%)
(RR, 1.6; 95% CI, 1.4-1.9; P<.001). Data from
spouses provided cumulative risk estimates of dementia in a population that
shared environmental, but not genetic, background with the proband. The cumulative
risk of dementia among spouses of white probands was 10.4% (1.7%) while for
spouses of African American probands it was 18.5% (8.4%) (RR, 1.8; 95% CI,
0.5-6.0; P = .34). The proportional increase of 2.4
(95% CI, 2.1-3.2) in risk between spouses and first-degree biological relatives
of African American probands was very similar to the proportional increase
of 2.6 (95% CI, 1.3-4.4) in risk between spouses and first-degree biological
relatives of white probands. Within ethnic groups, each of these comparisons
was significant (P<.005 for both).
As shown in Table 2 and Figure 2, among the first-degree biological
relatives of probands, women had a greater risk of dementia than men, within
each ethnic group. African American women had a 1.2-fold higher risk than
African American men (RR, 1.2; 95% CI, 0.9-1.7; P
= .30) while white women had a 1.5-fold higher risk than white men (RR, 1.5;
95% CI, 1.3-1.7; P<.001). The absolute increase
in risk among women compared with men was of similar magnitude within each
ethnic group as illustrated in Figure 4,
although it did not reach significance among African Americans.
Among the 980 white probands with APOE genotyping,
466 (47.6%) had 1 ∊4 allele and 124 (12.7%) had the ∊4/∊4 allele.
Among the 211 African American probands with APOE
genotyping, 95 (45.0%) had 1 ∊4 allele and 48 (22.7%) had the ∊4/∊4
genotype (Table 1). The risk of
AD among white and African American probands and its modification with the ∊4
allele is described in a separate report.10
As shown in Table 2 and Figure 3, the ∊4 status of the proband
altered the cumulative risk estimates of the relatives. For example, the presence
of a single ∊4 allele in the proband increased the risk in African American
relatives by 1.3 (95% CI, 0.9-2.5; P = .13) and in
white relatives by 1.5 (95% CI, 1.3-1.8; P<.001).
The presence of 2 ∊4 alleles in the proband increased the risk in African
American relatives by 1.8 (95% CI, 1.1-2.8; P = .01)
and in white relatives by 1.5 (95% CI, 1.1-2.0; P
= .008). As shown in Figure 3 and Figure 5, the pattern of increased risk in
relatives conferred by the presence of 1 or 2 ∊4 alleles in the proband
is similar between African American and white families even though with the
smaller sample size among the African Americans, the 95% CIs for 1 ∊4
allele include 1.
Because the educational level of the proband could be a considered a
proxy for the educational level of the relatives, the risk estimates in relatives
were stratified by educational level among both whites and African Americans
(data not shown). The risk estimates for relatives of African American probands
were higher within each strata of proband education than the same estimates
in whites. Therefore, educational levels of the probands do not confound the
risk differences observed between ethnicities.
In the clinical setting, family members of patients with AD realize
that AD has a heritable component, and they often ask the clinician for some
measure of their own risk. This report provides clinically relevant estimates
of dementia risk in a large clinic-based population of white and African American
families. These data confirm and enhance the precision of the cumulative risk
curves that we have already published for white families.5,6
Our large sample of African American families allows us to present, for the
first time, precise age-specific risks of dementia among first-degree biological
relatives of African American patients with AD. By examining the risk curves
for relatives in Figure 1, clinicians
can now ascertain empirical estimates of risk that may be useful for counseling
white and African American family members of AD patients.
Our data indicate that relatives of African American patients are 1.6
times more likely than relatives of white patients to become demented by age
85 years. This finding could potentially reflect a higher degree of familial
aggregation in African American families, a higher baseline risk of dementia,
or both. These possibilities can be distinguished by examining the risk of
dementia among spouses of our AD patients who are matched by age and share
many environmental determinants. We find that spouses of African American
patients with AD are 1.8 times more likely to develop dementia than spouses
of white patients, and that the proportionate additional risk conferred by being a first-degree relative is quite similar in
each ethnic group (2.6 in whites vs 2.4 in African Americans). Thus we conclude
that risk attributable to familial aggregation is very similar in African
American families and white families.
As shown in Table 2 and Figure 2, female relatives are at higher
risk than male relatives. Figure 4
suggests that while the risk associated with African American ethnicity is
much larger than that associated with sex of the relative, the degree to which
sex influences risk within each ethnic group is similar.
In the subset of AD patients for whom we assessed APOE genotype, we were also able to calculate risks in relatives stratified
by the genotype of the patient. Although the genotypes of the relatives themselves
were not available, this stratification serves as an estimate of the probability
of finding an ∊4 allele in the relatives of each strata.5Figure 3 and Figure 5 once again suggest that ethnicity is a more powerful risk
factor for dementia in relatives than the presence of an ∊4 allele in
the proband. And, although the curves implied in Figure 5 are not completely parallel, with relatively wide SEs around
the point estimates in the African American relatives, they too suggest that
the increase among relatives that can be attributed to the probability of
having an ∊4 allele is quite similar in both ethnic groups.
The only other study to estimate familial risk in African American families
solicited family history information from incident cases of AD and controls
in a community-based study of white, African American, and Caribbean Hispanics
in northern Manhattan.20,21 Devi
et al21 studied 57 white patients with AD with
219 relatives and 112 African American patients with AD with 362 relatives
but did not report cumulative risk estimates by ethnicity. They used Cox proportional
hazard analysis to adjust for proband's sex, educational level, and the sex
of the relatives, to calculate adjusted rate ratios. They found relatives
of white patients to have a rate ratio of 2.0 (95% CI, 1.2-3.3) compared with
the relatives of controls, and the relatives of African American patients
to have a rate ratio of 1.4 (95% CI, 0.7-2.7) compared with the relatives
of controls. No comparisons were drawn between the risks to African American
relatives and the risks to white relatives of AD patients. The magnitude of
the increase in risk between the relatives of their patients compared with
the relatives of their controls is similar to the magnitude of increased risk
among both white and African American relatives in our study in comparison
to spouses.
In a population of 101 white patients and 195 African American patients,
Devi et al20 also examined the additional risk
conferred by the presence of an ∊4 allele in the proband. Direct comparisons
with our results are not straightforward because they did not compare risk
across ethnic groups, and their data were stratified by the presence of at
least 1 ∊4 allele while ours were stratified into 3 groups (no, 1, or
2 ∊4 alleles). Among relatives of patients with AD, Devi et al found
that the presence of at least 1 ∊4 allele doubled the adjusted risk among
whites and tripled the adjusted risk among African Americans, which appears
consistent with our findings.
Our findings are based on cross-sectional data from clinic-based recruitment
at 17 major medical centers, within both large and small cities. Our findings
in African Americans are based on families recruited primarily in Atlanta,
Ga; Birmingham, Ala; Boston, Mass; and Charleston, SC. Although this sampling
scheme does not represent the population at large, it is an appropriate population
from which to derive risk estimates for family members of clinic-based AD
patients who are seeking risk information. African American probands and their
families were recruited in exactly the same way as white probands and their
families.
Our study has several limitations. It is possible that white and African
American informants might be differentially referred or self-referred to clinics,
or might differentially report dementia among family members. A selection
or reporting bias of this nature could explain some of the risk differences
that we found. There are few data on the differences in referral patterns
of African American and white families with affected members. However, there
are data to suggest that there is relative underreporting of cases among African
American families.22-24
If true, a bias of this nature would reduce the estimated risk of dementia
among African American relatives and bias the relative risks between white
and African Americans toward the null.
Data on educational level were not available for the relatives of probands,
and therefore the risk estimates presented herein could not be adjusted for
education. Educational level was available for the probands, and on average
the white probands in the study were more highly educated than the African
American probands. However, stratification by educational level of the proband
did not change the overall results.
Despite the large number of families overall, there are considerably
fewer African American probands and relatives, which, when stratified, result
in wide CIs. Also, the results of this study are most relevant to clinic-based
populations, particularly those at referral centers, and may be less representative
of families who are not evaluated by clinicians or who are evaluated in primary
care settings or in community practices.
The relatives of the affected probands in this study were often deceased
or unavailable so that the categorization of affected relatives was made on
the basis of historical information. Since most affected relatives lacked
a definitive diagnosis, we have described the familial risk of dementia rather
than ascribing a particular diagnosis such as AD to the relatives. Since cerebrovascular
risk factors such as hypertension and diabetes are more common among African
Americans, it is possible that differential rates of cerebrovascular disease
among African American relatives could explain some of the differences described
herein. Furthermore, we did not have measures of comorbid illness of the probands.
However, validation studies in other populations have produced evidence that
the family history method is valid and that cognitively impaired relatives
of AD patients overwhelmingly have AD.25,26
A number of epidemiological studies have examined the risk of dementia
or of AD in white and African American people, and recent studies have consistently
supported a higher age-specific prevalence of dementia,27
cumulative risk of AD,28 and incidence rates
of AD29 among African Americans compared with
non-Hispanic whites. Most relevant to our findings, Tang et al31
reported that the cumulative risk of AD among African Americans by age 90
years is 4 times that of whites.
The association between APOE genotype and risk
of AD is well established in white populations,2
and the association in African Americans is of great interest. A number of
studies have suggested a weaker association between ∊4 and AD in African
Americans than in whites30-32
as well as a weaker association among elderly Nigerians33
and Kenyans.34 The data on risk in family members
presented in this article do not address this question, but our analysis of APOE information from a large group of MIRAGE probands,
siblings, and unrelated controls indicates that ∊4 is an important risk
factor for AD in African Americans, particularly among those younger than
70 years.10 Taken together, our data suggest
that genetic factors other than APOE play an important
role in the heritable component of AD in both white and African American families.
Figure 1 and Figure 2 provide clinicians with information that can be used to
advise family members of patients with AD who ask about their own average
risk of developing dementia. Figure 1
provides a contrast between the average risk of a first-degree biological
relative and that of the general population, as estimated through the spouses
of probands, although this should be interpreted with caution because spouses
are not truly representative of the population at large and because the number
of affected African American spouses is so low. Figure 2 provides the most refined category of risk estimate, stratified
by ethnicity and sex. Because APOE genotyping is
not currently advocated to help estimate risk,35-40Figure 3 is of scientific interest but should
not be used for clinical counseling.
In conclusion, our findings in this report support the growing body
of data that risk of dementia and AD is higher in African Americans than in
whites.27,29 However, within each
ethnic group, the additional risk conferred by being a first-degree biological
relative, by being female, or by the probability of having an ∊4 allele
is of very similar magnitude. Our data provide estimates of dementia risk
that can be used to provide counseling to family members of patients with
AD.
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