An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease.
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Alleles↗
Biomedical subjects
W K Scott
Publications and source records attributed to W K Scott.
Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4 allele.
OBJECTIVE: Because subjective memory complaints may indicate subtle functional brain abnormalities, the authors studied the influence of the major genetic risk for Alzheimer's disease, the apolipoprotein E-4 (APOE-4) allele, on self-reports of memory performance in middle-aged and older adults. METHOD: Subjective and objective assessments of memory performance were compared in relation to the presence or absence of the APOE-4 allele in 39 cognitively intact persons with mild memory complaints. RESULTS: Subjects with the APOE-4 allele had lower scores on objective verbal memory and on the subjective memory measure for retrospective functioning. Among the subjects in the age range where APOE-4 has its greatest influence on the risk of Alzheimer's disease (55-74 years), the APOE-4 group had lower scores on the subjective memory measure for frequency of forgetting. Moreover, the standardized difference in retrospective functioning scores between the two genetic risk groups increased when the mid-age-range group was examined rather than the whole study group. CONCLUSIONS: The APOE-4 allele is associated with increased subjective memory impairment in middle-aged and older adults. Longitudinal studies of age-related memory loss should include genetic risk and subjective memory measures as potential predictors of decline.
Adult↗
Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson's disease.
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Adolescent↗
No association of alpha1-antichymotrypsin flanking region polymorphism and Alzheimer disease risk in early- and late-onset Alzheimer disease patients.
The alpha1-antichymotrypsin (AACT)-155 allele was found elsewhere to have a significant effect on Alzheimer disease (AD) risk in individuals with at least one APOE-4 allele. We compared AACT genotypes of 284 cases of sporadic AD and 172 controls. The frequency of the AACT-155 allele did not differ significantly between cases and controls, either overall or when restricted to subjects with at least one APOE-4 allele. Logistic regression controlling for age and sex failed to show an effect due to AACT either alone or acting with APOE. There was no evidence of an interaction between APOE-4 and the AACT-155 allele to reduce age at onset. Thus, our data do not support an association of AACT-155 with risk or age at onset in AD.
Adult↗
Association between bleomycin hydrolase and Alzheimer's disease in caucasians.
A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with non-demented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controlling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.
Aged↗
No genetic association between the LRP receptor and sporadic or late-onset familial Alzheimer disease.
The low-density lipoprotein receptor-related protein gene (LRP1) is often mentioned as a candidate gene for Alzheimer disease (AD) because of its role as a receptor for apolipoprotein E (apoE), a major genetic risk factor for late-onset familial and sporadic AD. A recent association study of a tetranucleotide repeat polymorphism located 5' to the LRP1 gene detected an increase in the 87 base pair allele in AD cases compared to unaffected controls. Additionally, an independent study involving a genomic screen for genes associated with late-onset AD identified a region as a possible location of a late-onset AD gene on chromosome 12p between D12S373 and D12S390, about 10 cM proximal to LRP1. We examined 144 late-onset multiplex AD families, 436 sporadic AD cases, and 240 controls and found no evidence of linkage or association of LRP1 and AD. Our data indicate that genetic variation of the LRP1 gene is not a major risk factor in the etiology of AD.
Age of Onset↗
Lack of association between apolipoprotein E genotype and sporadic amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neuro-degenerative disorder with both sporadic and familial forms. Approximately 20% of autosomal dominant ALS is caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The causes of the remaining forms of ALS are unknown. The apolipoprotein E (APOE) gene is a known genetic risk factor for Alzheimer disease (AD), another neuro-degenerative disease. The APOE-4 allele increases risk and decreases age at onset in AD. Studies examining ALS and APOE have failed to show a significant effect of APOE on overall risk in ALS. Studies examining the effect of APOE-4 on site of onset in ALS (bulbar or limb) have been contradictory, with some studies showing an APOE association with bulbar onset and others showing no effect. Sample size was limited in these previous reports, particularly with respect to the number of bulbar onset cases (n = 33, 34 and 53). The present study examines a large collaborative data set of ALS patients (n = 363; 95 with bulbar onset) and age-matched neurologically normal controls. The results for these data showed no significant differences in the percentage of subjects with the APOE-4/4 and APOE-4/X genotypes (X = APOE-2 or APOE-3) when comparing cases and controls in both the overall data set or in the data set stratified by site of onset. Similarly, logistic regression analysis in the overall and stratified data set while controlling for sex showed no increase or decrease in risk of ALS associated with the APOE-4 allele. In addition, there were no significant differences in age at onset between patients with APOE-X/X, and APOE-4/4 or APOE-4/X genotypes, overall or stratified by site of onset. We conclude based on these data that the APOE gene is not a major genetic risk factor for site of onset in ALS.
Adult↗
Evidence for anticipation in autosomal dominant limb-girdle muscular dystrophy.
Anticipation, an increase in severity or decrease in age of onset (AO) inherent in the transmission of the disease gene from affected parent to affected child, has been increasingly described in human disease. To assess anticipation in a large kindred in which autosomal dominant limb-girdle muscular dystrophy (LGMD1A) is segregating, age of disease onset was collected from patient interviews of affected family members. A total of 25 parent-offspring pairs, in which the parents are three (3R), four (4R), or five (5R) generations removed from a common founding ancestor, were available for analysis. Life table analyses showed significant decreases in age at first reported symptoms in the offspring of the 3R (chi2=5.55, p=0.02) and 4R (chi2=7.81, p=0.005) parents. Pairwise analyses confirmed this decrease with a median decrease of 13 years in transmission to offspring from 3R parents and 18 years in transmission to offspring from 4R parents. The finding of anticipation in this pedigree suggests that the mutation in LGMD1A may be the result of the expansion of an unstable trinucleotide repeat.
Adult↗
Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12.
CONTEXT: Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. OBJECTIVE: To identify additional genetic risk factors for late-onset AD. DESIGN: A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. SETTING: Clinic populations in the continental United States. PATIENTS: From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. MAIN OUTCOME MEASURES: Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods. RESULTS: Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9. CONCLUSIONS: A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.
Age of Onset↗
Genetic complexity and Parkinson's disease. Deane Laboratory Parkinson Disease Research Group.
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Adult↗
Genetic analysis of complex diseases.
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Chromosome Mapping↗
No association or linkage between an intronic polymorphism of presenilin-1 and sporadic or late-onset familial Alzheimer disease.
Recent reports have shown an association between an intronic polymorphism of the presenilin-1 (PSEN1) gene and late-onset (age at onset > 65) familial and sporadic (no family history) Alzheimer disease (AD). The reported association was independent of the effect of the only previously identified gene associated with late-onset AD, APOE. Blood samples were obtained from members of 122 multiplex AD families, 42 unrelated cases of AD with positive family histories of dementia, 456 sporadic cases of AD, and 317 controls of similar ages at examination to the cases. These samples were genotyped for an intronic polymorphism of the PSEN1 gene, located 3' to exon 8, and the data analyzed for evidence of association or linkage. The samples were also genotyped for APOE and the data analyzed to see if the association or linkage changed when controlling for APOE genotype. There was no statistically significant increase (at alpha = .01) in allele 1 (199 bp) or genotype 1/1 in the sporadic AD cases, or in a random sample of one affected from each multiplex family, compared to controls. When examining the effect of the PSEN1 polymorphism while controlling for APOE genotype, APOE genotype was strongly associated with AD, but the PSEN1 polymorphism genotype was not. Model-trait dependent (lod score) and independent (Sim1BD) methods detected no evidence of linkage between PSEN1 and AD. In this independent dataset, the previously reported association between the intronic PSEN1 polymorphism and AD cannot be confirmed, and the conclusion that PSEN1 is a major susceptibility gene for late-onset AD is not supported.
Age of Onset↗
False positive rates in a genomic screen for complex quantitative traits.
We conducted a genomic screen for genes associated with Q1, Q2, and Q3 in 239 nuclear pedigrees from replicate 115, Problem Set 2A. We compared false positive (FP) and true positive (TP) rates for three significance levels and two map densities. Using the 2 cM genetic map and alpha = 0.05 produced the most FP but detected the greatest number of major genes. Following up only 31 plateaus (two or more adjacent markers with significant results) from the 2 cM screen eliminated some FP, but failed to detect MG3 for Q3. Multipoint analysis reduced the number of priority regions from 31 to seven; only two of these regions were TP. Replication of the two-point analysis of plateau markers in replicate 80 detected all of the genes associated with Q1 and Q2, but not Q3. Multipoint analysis in replicate 80 failed to replicate any genes associated with Q1, Q2, or Q3, but "replicated" two FP regions. While FP may be reduced by decreasing map density, considering only plateaus for follow up and decreasing significance levels, such adjustments may also fail to detect weak TP. Multipoint analysis and replication in independent data sets may not be reliable methods of distinguishing FP from TP.
Chromosome Mapping↗
Apolipoprotein E epsilon2 does not increase risk of early-onset sporadic Alzheimer's disease.
We examined the association of apolipoprotein E (ApoE) genotype and the risk of early-onset Alzheimer's disease (AD) in 209 white early-onset sporadic cases (43% male) and 303 white controls (48% male) of similar age distribution. The risk of AD was significantly increased, relative to the 3/3 genotype, in people with the 4/4, 3/4, and 2/4 genotypes, controlling for age at time of examination and sex. The 2/3 genotype reduced slightly the risk of AD, although the effect was not statistically significant. We conclude, contrary to some previous reports, that the ApoE epsilon2 allele does not increase the risk of early-onset sporadic AD.
Adult↗
Locus heterogeneity, anticipation and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia.
We examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogeneity analysis of combined chromosome 2p and 14q data gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p<0.0001).
Adolescent↗
Functional health status as a predictor of mortality in men and women over 65.
This study evaluated the effect of functional health status on mortality in a sample of community-dwelling older people. White and African-American self-respondents to the 1986 National Health Interview Survey Functional Health Supplement (n = 5, 320) were included in the study. Functional health status was measured by a ten-item unidimensional activities of daily living-instrumental activities of daily living (ADL-IADL) scale and a three-item cognitive ADL scale. Proportional hazards regression was used to evaluate the effect of increasing score on the ten-item ADL-IADL scale on risk of mortality over a 5-year period while controlling for demographic, social, and health status covariates. In both men and women, increasing score on the ADL-IADL scale was predictive of mortality, adjusting for increasing age, poor self-rated health, low body mass index in women, and being an unmarried man. These findings indicate that a unidimensional scale consisting of both ADL and IADL items is useful in predicting mortality, controlling for the effect of covariates in sex-specific models.
Activities of Daily Living↗
Major depression and all-cause mortality among white adults in the United States.
PURPOSE: Depression is the most common psychiatric illness affecting adults. Despite the importance of a potential link between major depression and mortality, research has been surprisingly sparse. METHODS: Information on 57,897 white adults aged 25 years and older who were included in the mental health supplement of the 1989 National Health Interview Survey was linked with the National Death Index to examine the relationship of major depression to mortality. Death status was obtained through December 1991. Sex-specific hazard rate ratios for mortality were calculated by Cox proportional hazards regression and Poisson regression to adjust for potential confounders (age, education, marital status, body mass index, and whether the target subject or a family member completed the survey about the subject). RESULTS: Major depression was reported for 223 (0.8%) of 27,345 men and 392 (1.3%) of 30,552 women. During the 2.5-year follow-up, death certificate data were obtained for 848 (3.1%) men and 651 (2.1%) women. The adjusted hazard rate ratios for all-cause mortality associated with major depression were 3.1 (95% confidence interval; 2.0-4.9) for men and 1.7 (95% confidence interval; 0.9-3.1) for women. CONCLUSIONS: These results suggest that major depression increases risk of all-cause mortality, particularly among men. Further research is needed to explain the mechanism.
Adult↗
Risk of institutionalization among community long-term care clients with dementia.
South Carolina Community Long-Term Care (CLTC) data were used to identify factors increasing the risk of institutionalization in people with dementia. Clients diagnosed with dementia and observed at least twice between June 1993 and December 1994 (N = 786) were studied. Logistic regression determined that clients with a decline in ADL function who were white, had a nonrelative or child as a caregiver, and were diagnosed with Alzheimer's disease were at increased risk of institutionalization. Identifying CLTC clients at increased risk of institutionalization could be useful in designing additional interventions to prevent institutionalization or in planning the transition to institutional care.
Activities of Daily Living↗