RESUMO
Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.
Assuntos
Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 18/genética , Hispânico ou Latino/genética , Idoso , Apolipoproteína E4 , Apolipoproteínas E/genética , Região do Caribe/etnologia , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , República Dominicana/epidemiologia , Feminino , Ligação Genética/genética , Predisposição Genética para Doença , Genótipo , Humanos , Escore Lod , Masculino , New York/epidemiologia , Linhagem , Porto Rico/epidemiologiaRESUMO
OBJECTIVE: To investigate the heritability of memory and other cognitive measures in families with multiple individuals with Alzheimer disease (AD) to determine if neuropsychological measures can be used to better understand genetic contributions to AD. METHODS: The genetic contributions to the variation in declarative memory, attention, abstract reasoning, language, and visuospatial function using a variance component method were estimated. For memory scores, the proportion of genetic contribution was estimated, controlling for APOE. RESULTS: The unadjusted heritability estimates for the declarative memory tasks ranged from 0.47 for delayed recall to 0.25 for delayed recognition, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability score of 0 indicates that genetic factors explain none. When adjusted for sex, age, education, and general intelligence, the heritability estimates increased to 0.60 for delayed recall and 0.41 for delayed recognition. None of the other cognitive tests showed heritability estimates as high as that observed for memory. When the influence of APOE was taken into account, the heritability estimates changed modestly for delayed recall and consistent long-term retrieval, whereas the estimates for other memory scores did not change, suggesting that APOE contributes little to these memory scores. CONCLUSIONS: Declarative memory in familial AD is under strong genetic influence, only part of which is attributable to APOE. Memory performance should prove to be a useful phenotypic component in the investigation of the genetic basis of AD.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Proteínas de Membrana/genética , Transtornos da Memória/genética , Idoso , Alelos , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Região do Caribe , República Dominicana , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Cidade de Nova Iorque , Presenilina-1 , Porto RicoRESUMO
CONTEXT: Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. OBJECTIVE: To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. DESIGN AND SETTING: Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. PATIENTS: Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. MAIN OUTCOME MEASURE: The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. RESULTS: A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. CONCLUSIONS: The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.
Assuntos
Doença de Alzheimer/genética , Hispânico ou Latino/genética , Proteínas de Membrana/genética , Idade de Início , Idoso , Alanina , Doença de Alzheimer/epidemiologia , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Região do Caribe/etnologia , Análise Mutacional de DNA , República Dominicana/etnologia , Éxons , Genótipo , Glicina , Haplótipos , Humanos , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Fenótipo , Polimorfismo Genético , Presenilina-1 , Porto Rico/etnologia , Estados Unidos/epidemiologiaRESUMO
As the US population of elderly Hispanics continues to grow, there is an increasingly greater need for neuropsychological measures that are appropriate for assessing Spanish-speaking elders. The current study compared the performance of randomly selected, community-based samples of English- and Spanish-speaking elders on a brief neuropsychological test battery. Subject groups were matched for age and education. Multivariate analysis indicated significant group differences on the test battery. English and Spanish speakers scored comparably on many language-based tasks, but Spanish speakers scored significantly lower on almost all of the nonverbal measures. Significant group differences were observed on multiple-choice matching and recognition memory for stimuli from the Benton Visual Retention Test, as well as on Identities and Oddities from the Mattis Dementia Rating Scale, category fluency, and Complex Ideational Material from the Boston Diagnostic Aphasia Examination (BDAE). Results suggest that caution is warranted when using nonverbal as well as verbal measures to assess non-English-speaking individuals.