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Familial Alzheimer Disease Among Caribbean Hispanics
A Reexamination of Its Association With APOE
Stavra N. Romas, MD;
Vincent Santana, BA;
Jennifer Williamson, MS;
Alejandra Ciappa, BS;
Joseph H. Lee, PhD;
Haydee Z. Rondon, MD;
Pedro Estevez, MD;
Rafael Lantigua, MD;
Martin Medrano, MD;
Mayobanex Torres, MD;
Yaakov Stern, PhD;
Benjamin Tycko, MD, PhD;
Richard Mayeux, MD, MSc
Arch Neurol. 2002;59:87-91.
ABSTRACT
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Objectives To reexamine the association between the apolipoprotein E  4 allele
(APOE 4) and familial Alzheimer disease (AD),
and to search for novel genes that may be associated with susceptibility in
Caribbean Hispanic families with a history of AD.
Methods Families were identified in Caribbean Hispanic communities in the greater
New York City area, the Dominican Republic, and Puerto Rico. Each family in
the study cohort included at least 2 living relatives with a history of dementia.
All family members underwent neuropsychological testing and medical and neurological
examinations to establish the presence or absence of dementia and to specify
the type of dementia.
Results Over a 2 -year period, 203 families were identified. Of these,
19 families had at least 1 family member with onset of dementia before age
55 years, with 8 of the 19 families showing an association with a previously
unreported presenilin mutation. Multiple cases of AD were identified in 29
families. Overall, there were 236 affected sibling pairs with AD available
for analysis. The average age at onset was 74 years. The presence of APOE 4 was strongly associated with AD.
Conclusions Both early-onset and late-onset familial AD occur in Caribbean Hispanics.
In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics
is strongly associated with APOE 4. Future
attempts to identify additional susceptibility genes should consider the effects
of APOE 4.
INTRODUCTION
A FAMILY HISTORY of Alzheimer disease (AD) is one of the strongest risk
factors for the disease. The lifetime risk of AD for family members of patients
approaches 50% in some studies, which suggests an age-dependent autosomal
dominant mode of inheritance.1-2
Mutations in genes on chromosomes 1, 14, and 21 are associated with familial
early-onset AD, often with an autosomal dominant pattern of inheritance.3-4 However, these genes account for only
10% of all AD. The discovery that a polymorphism in the APOE (apolipoprotein E) gene on chromosome 19 was associated with susceptibility
to both sporadic and familial late-onset AD5
led to the search for other potential susceptibility genes. Sites for potential
susceptibility genes on chromosome 12 have been identified,6
and, more recently, sites on chromosome 10 have also been identified.7-9 Attempts to confirm
the linkage between chromosome 12 and AD have been variable,10-12
and the association with  2-macroglobulin, a candidate gene
in the area, has also been inconsistent.13-16
Familial AD may be the result of complex inheritance involving many genes
with incomplete penetrance or a combination of genetic and environmental factors.
Hispanics are one of the most rapidly increasing ethnic groups in the
United States. The elderly Hispanic population is expected to double in the
United States by the year 2010 and increase 11-fold by 2050.17
Compared with other ethnic groups, Caribbean Hispanics have an increased prevalence
and incidence of AD,18-20
as do Mexican Americans.21 Yet the reason for
this increase in disease frequency is unknown. No specific environmental factors
have been identified, which suggests a genetic explanation.
The association between AD and the APOE 4
allelic polymorphism has been weaker in late-onset AD among Caribbean Hispanics
compared with whites in New York City20, 22-23
but not in Miami, Fla.24-25 We
began the family study not only to identify the chromosomal location of additional
susceptibility genes in Caribbean Hispanics, but also to reinvestigate the
heterogeneity of the APOE association in this population.
PARTICIPANTS AND METHODS
SOURCE POPULATION AND RECRUITMENT
Recruitment for the family study began in 1998. All patients in a population-based,
community study of dementia in the Washington Heights–Inwood community,
New York City, were eligible if they met inclusion criteria for our study.
Patients were identified through registry information on 1330 individuals
and a survey of 2250 Medicare recipients taken as a random sample from the
community. Patients were also recruited from The Alzheimer Disease Research
Center/Memory Disorders Center, from physicians' private offices in the Department
of Neurology, and from the General Medical Services, Columbia University,
New York City. We used local newspapers, the local Hispanic radio station,
and postings throughout Washington Heights–Inwood. Lectures were given
at each of the 10 senior centers in the community. A system of recruitment
was also set up in the Dominican Republic with the help of several local physicians,
including the president of the Dominican Society of Geriatrics and Gerontology.
Some investigators made annual visits to the Dominican Republic and Puerto
Rico to fully assess all eligible families.
ASCERTAINMENT OF PROBANDS AND SIBLINGS
Once patients with AD were identified, their illnesses were documented
with standardized neurological and neuropsychological evaluations. Then, structured
family history interviews were conducted with available family members to
determine whether patients had living siblings or relatives with the disease.
We had previously established that reliability and validity of family history
of AD among first-degree relatives was high.26
If the family history interview revealed a living sibling with suspected AD,
that individual was also interviewed and examined. If a sibling of the proband
had dementia, all other living siblings and available relatives were evaluated
with the same examinations.
CLINICAL DIAGNOSIS
Medical and neurological examinations were completed for all family
members, and patients were required to meet National Institute of Neurological
and Communicative Disorders and Stroke and the Alzheimer's Disease and Related
Disorders Association (NINCDS-ADRDA) research criteria for probable or possible
AD.27 The Clinical Dementia Rating Scale (CDR)28 was used to rate the severity of dementia. A CDR
score of 0 indicated no dementia; 0.5, questionable; 1, mild; 2, moderate;
and 3, severe. Brain imaging and other laboratory studies were reviewed when
available and offered when medically necessary to ensure full implementation
of the NINCDS-ADRDA criteria. All patients in the Dominican Republic were
offered the same diagnostic evaluations if deemed necessary.
The neuropsychological examinations used included a battery of tests
modified for use with Spanish speakers.29-30
The tests included the Selective Reminding Test31;
Benton Visual Retention Test, Matching and Recognition Memory32;
the Orientation section of the Mini-Mental State Examination33;
the Rosen Drawing Test34; the Boston Naming
Test35; the Controlled Word Association Test36; the first 6 items of the Complex Ideational Material
subtest of the Boston Diagnostic Aphasia Evaluation 37;
Wechsler Adult Intelligence Scale–Revised (Similarities section)38; and the Identities and Oddities subtest of the Mattis
Dementia Rating Scale.39
Clinical data were reviewed at a consensus conference of neurologists
and neuropsychologists. These methods and their development have been previously
described.29-30,39
We included all those probands and siblings with probable AD, including those
with CDR scores of 0.5. Our conservative definition of AD required a diagnosis
of probable AD and a CDR score of 1 or more. Our liberal definition included
participants with CDR scores of 0.5 or less who also met our neuropsychological
criteria for probable AD but did not have functional impairment at the time
of evaluation. Results from the 2 groups were compared for our study of APOE.
DNA COLLECTION AND APOE GENOTYPES
We collected blood from all patients with AD, their living siblings,
and other family members. A modification23
of the methods described by Hixson and Vernier40
was used to determine APOE genotypes.
ASSOCIATION ANALYSIS
To examine whether the APOE 4 allele
was transmitted more frequently in individuals with AD than by chance, we
conducted a sibling transmission disequilibrium test (sib-TDT).41
Although the sib-TDT is conceptually comparable to the original transmission
disequilibrium test (TDT),42 it allows testing
of the transmission probability when parent genotype data are not available.
As with the TDT, the sib-TDT determines association in the presence of linkage
and avoids the problems of population stratification. To be used in the analysis,
however, this method requires sibships to have at least 1 affected and 1 unaffected
sibling; they should also have different genotypes.
RESULTS
During the first 2 years of the project, 203 families were recruited.
We divided extended families into multiple nuclear families. The majority
of the families (81.3%) classified themselves as from the Dominican Republic,
24 (11.8%) were from Puerto Rico, and 14 (6.9%) came from elsewhere in the
Caribbean. Overall, there were 728 individuals (241 men and 487 women) we
examined and from whom we obtained DNA (Table 1). According to our conservative definition of AD, 306 participants
(85 men and 221women) had probable AD, and 218 were unaffected. Unaffected
individuals were defined as those who were diagnosed without dementia at an
age comparable to the probands. Of the remainder, 132 had CDR scores of 0.5,
and 72 had other diagnoses of dementia. An additional 63 individuals were
coded as diagnosis unknown either because they had not been examined by us
or because they were under age 40 years.
Nineteen families had at least 1 individual with onset of AD before
age 55 years. We found a presenilin mutation in exon 7 in 8 (4%) of these
families,43 and these 8 families were excluded
from the sib-TDT analysis. In 29 families, multiple cases of AD were identified
(Table 2). When we used a conservative
definition of AD, there were 236 affected sibpairs. Eight families had 5 or
more affected individuals, 4 families had more than 4 affected individuals,
and 17 families had at least 3 affected family members. Sixty-three families
had at least 2 affected individuals. The remaining 111 families had at least
1 affected individual who also had a mildly impaired relative. Finally, 81
families had at least 1 affected and 1 unaffected individual with APOE data, and 47 of these had at least 1 affected and 1 unaffected
individual with different APOE genotypes.
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Table 2. Pedigree Structures
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Allele frequencies and APOE genotypes for both
affected and unaffected individuals are provided in Table 3. The APOE 4 allele was more
likely to be transmitted among affected individuals than unaffected relatives
(Table 4). The transmission probability
of APOE 2 was not significantly different from
the null (Table 4). Because this
study includes more than 200 families, the use of normal approximation is
justified. This analysis is not a valid test of association, but it does represent
a valid test of linkage.41
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Table 3. APOE Allele and Genotype Frequencies*
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Table 4. APOE Transmission*
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COMMENT
We identified a large number of Caribbean Hispanic families with more
than 1 individual with AD, including 8 with early-onset AD associated with
a presenilin mutation.43 A much stronger association
between AD and APOE 4 was observed in these
families than was previously found among elderly Caribbean Hispanics with
late-onset sporadic AD.20, 23, 44
In a longitudinal cohort study using the APOE 3/3
genotype as the reference, the relative risk of developing AD at age 90 years
associated with 1 or more APOE 4 alleles was
1.1, and 0.7 to 1.6 for Caribbean Hispanics with AD.20
However, the cumulative risk of AD at age 90 years among Caribbean Hispanics
with an APOE 4 allele was similar to that in
whites, whereas in the absence of an APOE 4
allele, Caribbean Hispanics were 2 times to 4 times more likely than whites
to develop AD.20 The time-to-event variable
was age at onset of AD, which required no further age adjustment. The increase
in risk was not related to differences in education or the presence of other
risk factors such as a family history of AD-like dementia, suggesting that
other genes or unknown factors may be involved.
There are at least 2 potential explanations for the differences in association
between AD and APOE 4 in these 2 studies. The
community study included elderly individuals who were selected because they
were residents of Washington Heights–Inwood and were registered Medicare
recipients. The families in the current investigation were selected because
they had at least 2 living family members with AD and were not from a single
community. It is likely that the inclusion of individuals with familial AD
enriched the association with APOE 4, a point
that has been noted previously.24 Compared
with our previous study,20 the APOE 4 allele frequency for controls in the current study was
40% higher (23.2% vs 14.1%); in cases the frequency increased by 54% (32.4%
vs 14.8%). In addition, we previously found an increased risk for family members
of patients with an APOE 4 allele compared
with other genotypes.45 Second, the average
age at onset for AD in the current family study was 73.7 years, while the
average age at onset was 81.4 years among Caribbean Hispanic patients residing
in Washington Heights. Both results are consistent with what is already known
about the effect of APOE 4 on the age at onset
of AD and its relationship to familial and sporadic forms of the disease.46
Farrer et al46 completed a worldwide
meta-analysis of the relationship between APOE 4
and AD described in numerous published and unpublished studies. They concluded
that APOE 4 was an important determinant of
AD risk for men and women older than 60 years, but the association weakened
after age 85 years. They also confirmed that APOE 4
was strongly related to AD risk among whites and Asians. However, the relationship
among African Americans and Hispanics remained inconsistent and weak in comparison,
which supports our earlier findings. It is likely that the genetic influences
for late-onset sporadic AD differ from those related to familial AD occurring
earlier in life.
Studies examining the association between AD and APOE 4 in Spain47-48
are consistent with results from other American and European studies. In contrast,
Caribbean Hispanics from the Dominican Republic and Puerto Rico have a complex
genetic heritage that differs from that of European Hispanics. First invaded
by Spanish explorers, the Caribbean islands experienced political domination
by Spanish, French, and British colonists for more than 500 years. Moreover,
Africans captured as slaves were brought to the Caribbean during the same
period. Our studies indicate that among Caribbean Hispanics from the Dominican
Republic and Puerto Rico, sporadic AD is only weakly associated with APOE 4, while familial AD is more strongly associated.
Similar results have been found among Caribbean Hispanics from Cuba.24-25,49
We have previously studied 2 candidate genes in these families: an intronic
polymorphism in presenilin 1 and a 5 base-pair deletion in the 2-macroglobulin gene,16, 50
both of which have shown associations with AD in previous family-based and
case-control studies of other populations. The 2-macroglobulin
deletion showed initial evidence of a weak association in this population,16 but it has not been confirmed by other studies.14-15 The presenilin 1 polymorphism showed
no evidence of association or linkage with AD in this population.50
Although it is possible that some as yet unidentified environmental
factors have a causal role in the higher frequency of AD among Caribbean Hispanics,
the weight of evidence suggests that AD is a predominantly genetic disorder.
DNA from the families described here will be used in a genome-wide scan to
search for the chromosomal location of other genes that may be associated
with susceptibility to AD. The strong association between AD and APOE 4 will require analyses to stratify for this allele.
AUTHOR INFORMATION
Accepted for publication August 30, 2001.
Author Contributions: Study concept and
design (Drs Romas and Mayeux and Mr Santana);acquisition of
data (Drs Romas, Rondon, Estevez, Lantigua, Medrano, Torres, Tycko,
and Mayeux, Mr Santana, and Mss Williamson and Ciappa); analysis and
interpretation of data (Drs Romas, Lee, Stern, Tycko, and Mayeux and
Ms Ciappa); drafting of the manuscript (Drs Romas, Lee, and Mayeux); critical revision of the manuscript for important intellectual content
(Drs Romas, Rondon, Estevez, Lantigua, Medrano, Torres, Stern, Tycko, and
Mayeux, Mr Santana, and Mss Williamson and Ciappa); statistical expertise (Drs Romas, Lee, Stern, and Mayeux); obtained funding
(Drs Romas and Mayeux); administrative, technical, and material support (Drs Romas, Rondon, Estevez, Lantigua, Medrano, Torres, Tycko, and
Mayeux, Mr Santana, and Mss Williamson and Ciappa); study supervision (Drs Romas, Lantigua, Tycko, and Mayeux); genotyping
(Ms Ciappa).
This study was supported by grants AG15473, AG08702, and AG07232 from
the National Institutes of Health, Bethesda, Md, the Charles S. Robertson
Memorial Gift for Alzheimer's Disease Research from the Banbury Fund, and
the Blanchette Hooker Rockefeller Foundation, New York City.
Corresponding author and reprints: Richard Mayeux, MD, MSc, Gertrude
H. Sergievsky Center, Columbia University, 630 W 168th St, New York, NY 10032
(e-mail: rpm2{at}columbia.edu).
From the Taub Institute for Research on Alzheimer's Disease and the
Aging Brain (Drs Romas, Rondon, Estevez, Lantigua, Stern, and Mayeux, Mr Santana,
and Ms Williamson), the Gertrude H. Sergievsky Center (Drs Romas, Lee, Rondon,
Estevez, Lantigua, Stern, and Mayeux, Mr Santana, and Ms Williamson), the
Departments of Medicine (Dr Lantigua), Neurology (Drs Romas and Mayeux), Pathology
(Dr Tycko and Ms Ciappa), and Psychiatry (Dr Mayeux), College of Physicians
and Surgeons, and the Division of Epidemiology, Mailman School of Public Health
(Drs Lee and Mayeux), Columbia University, New York, NY; the Universidad Tecnologica
de Santiago, Santiago (Dr Medrano), and the Plaza de la Salud, Santo Domingo
(Dr Torres), Dominican Republic.
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