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G D Schellenberg

Publications and source records attributed to G D Schellenberg.

At least 91 records · Page 5Linked to original sources
PubMed1995

A familial Alzheimer's disease locus on chromosome 1.

The Volga German kindreds are a group of seven related families with autosomal dominant early-onset Alzheimer's disease (AD). Linkage to known AD-related loci on chromosomes 21 and 14 has been excluded. Significant evidence for linkage to AD in these families was obtained with D1S479 and there was also positive evidence for linkage with other markers in the region. A 112-base pair allele of D1S479 co-segregated with the disease in five of seven families, which is consistent with a common genetic founder. This study demonstrates the presence of an AD locus on chromosome 1q31-42.

Adult↗
PubMed1995

Apolipoprotein E genotypes and age of onset in early-onset familial Alzheimer's disease.

The effect of the apolipoprotein E (APOE) epsilon 4 allele on age of onset was analyzed in two groups of families with early-onset Alzheimer's disease (AD), (1) Volga German (VG) kindreds, in which AD is caused by an unknown locus and (2) early-onset non-VG families showing evidence of linkage to chromosome 14. The epsilon 4 allele did not have a detectable effect on age of onset in either group. This finding suggests some forms of early-onset familial AD are not modifiable by APOE status, or that AD can be caused by APOE-independent pathways.

Age of Onset↗
PubMed1995

Progress in Alzheimer's disease genetics.

Three genetic loci for Alzheimer's disease have been identified. These are the amyloid precursor gene on chromosome 21, a gene for early-onset autosomal dominant Alzheimer's disease on chromosome 14, and the risk-modifying gene APOE on chromosome 19. Additional Alzheimer's disease genes remain to be found. The genes identified by studying inherited forms of Alzheimer's disease are now being used to understand the initiating steps in the pathogenesis of the disease.

Aged↗
PubMed1995

Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study.

OBJECTIVE: The joint effects of total cholesterol (TC) levels and the APOE genotype in Alzheimer's disease (AD) were evaluated because of previous reports that the APOE locus epsilon 4 allele was associated with both late-onset AD and elevated TC. DESIGN: Logistic regression was used to determine the effects of the APOE genotype, TC, age, and sex on prediction of AD in a community-based study of 206 cases and 276 controls. RESULTS: The relationship of the APOE genotype and AD was dependent on TC, age, and sex. However, current TC level does not fully explain the epsilon 4-Alzheimer's disease association. Affected men with higher TC and age under 80 years had the highest epsilon 4 allele frequencies. The epsilon 4 frequency declined significantly with age. SIGNIFICANCE: A pathologic role of higher TC or cholesterol-based differential survival of epsilon 4-carrying individuals may be involved in the relationship of the epsilon 4 allele with AD. The observed association of the APOE genotype and AD is expected to depend on the age, sex, and TC distributions of a given sample.

Aged↗
PubMed1995

Molecular genetics of familial Alzheimer's disease.

Defective genes play an important role in some, if not all cases of Alzheimer's disease (AD). Epidemiologic case control studies, family pedigree analysis, and recent twin studies clearly implicate inherited gene defects in development of the disease. In addition to defective genes, trisomy 21 also results in the neuropathology of AD and an increased risk of early dementia. The genetics of AD have been partially resolved. In some rare kindreds, AD is inherited by an autosomal dominant mechanism. In some of these rare families, mutations in the amyloid precursor protein (APP) gene on chromosome 21 are responsible for AD. APP mutations appear to account for approximately 5% of early-onset familial AD (FAD). Linkage analysis and a genomic scanning strategy have been used recently to localize an early-onset FAD locus to chromosome 14q24.3. This, as yet unidentified gene, accounts for FAD in most of the early-onset FAD kindreds which do not carry APP mutations. The chromosome 14 FAD locus is found in ethnically diverse populations including European Caucasians, Hispanics from Mexico, and in at least 1 Japanese family. However, the chromosome 14 locus is not responsible for FAD in the Volga German FAD families, a group of ethnically related kindreds with family age-of-onset means ranging from 50 to 65 years. Also, the chromosome 14 locus does not appear to be responsible for late-onset FAD. A locus on chromosome 19 appears to be a risk factor for AD in at least some late-onset FAD kindreds.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗
PubMed1994

Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2).

A genomic clone for the human heat shock protein (HSP) 70 gene located on chromosome 14 was isolated and sequenced. The gene, designated HSPA2, has a single open reading frame of 1917 bp that encodes a 639-amino acid protein with a predicted molecular weight of 70,030 Da. Analysis of the sequence indicates that HSPA2 is the human homologue of the murine Hsp70-2 gene with 91.7% identity in the nucleotide coding sequence and 98.2% in the corresponding amino acid sequence. HSPA2 has less amino acid homology to other members of the human HSP70 gene family, 83.3% to the heat-inducible HSP70-1 gene and 86.1% with the human heat shock cognate gene HSC70. HSPA2 is constitutively expressed in most tissues, with very high levels in testis and skeletal muscle. Significant but lower levels are also expressed in ovary, small intestine, colon, brain, placenta, and kidney. A yeast artificial chromosome (YAC) clone containing HSPA2 (YAC741H4) that also contained the polymorphic marker D14S63 was identified. This 670-kb YAC was mapped to 14q24.1 by fluorescence in situ hybridization (FISH). Subsequent two-color FISH and genetic mapping placed HSPA2/D14S63 proximal to the markers D14S57 and D14S77.

Amino Acid Sequence↗
PubMed1993

The Seattle Alzheimer's disease data set.

Forty families submitted to Genetic Analysis Workshop 8 are described. These are the families in the Seattle data set which have been typed for at least one genetic marker from the centromeric region of chromosome 21 or the q arm of chromosome 19. Thirteen of these families have average ages of onset below age 61 and are therefore considered to be early onset families. Seven of the families are of Volga German descent. Thirty-four of the families have autopsy documented Alzheimer's disease, including all 13 of the early onset pedigrees. The data set includes both the clinical and pedigree information available on the portions of the pedigrees used in the linkage analyses, genotype data on three loci on chromosome 19 and four loci on chromosome 21, and more extended family data on individuals who have not been included in the linkage analyses.

Adult↗
PubMed1993

Chromosome 14 and late-onset familial Alzheimer disease (FAD).

Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset > or = 60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score < or = -2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P < .02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset > or = 60 years and < 70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds.

Adult↗
PubMed1992

Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.

Linkage analysis was used to search the genome for chromosomal regions harboring familial Alzheimer's disease genes. Markers on chromosome 14 gave highly significant positive lod scores in early-onset non-Volga German kindreds; a Zmax of 9.15 (theta = 0.01) was obtained with the marker D14S43 at 14q24.3. One early-onset family yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made about age-dependent penetrance, significant results were still obtained (Zmax = 5.94, theta = 0.0), despite the loss of power to detect linkage under these conditions. Results for the Volga German families were either negative or nonsignificant for markers in this region. Thus, evidence indicates a familial Alzheimer's disease locus on chromosome 14.

Alzheimer Disease↗
PubMed1992

Genetic association and linkage analysis of the apolipoprotein CII locus and familial Alzheimer's disease.

We previously reported a genetic association between the 3.5 kb (F) Taq I restriction fragment length polymorphism allele of the apolipoprotein CII gene on chromosome 19 and familial Alzheimer's disease. Here, we report an additional analysis of this association performed on an expanded and better defined data set of 23 families with familial Alzheimer's disease. The F allele frequency in affected family members in the expanded set was 0.62 +/- 0.06 (mean +/- standard error, n = 51 subjects), which differed significantly from a frequency of 0.39 +/- 0.02 (n = 226) for unrelated control subjects (Z = 3.75, p less than 0.0002). These results are consistent with our previous findings and suggest an association between the F allele of apolipoprotein CII and familial Alzheimer's disease. When the apolipoprotein CII locus was tested for linkage to familial Alzheimer's disease, LOD scores summed for the complete group of families were negative and close linkage was excluded. Close linkage was also excluded for early-onset families (mean onset age less than or equal to 60 years), but small positive LOD scores were obtained for late-onset kindreds.

Alleles↗
PubMed1992

Increased platelet membrane fluidity as a diagnostic marker for Alzheimer's disease: a test in population-based cases and controls.

To test whether increased platelet membrane fluidity as measured by decreased steady state fluorescence anisotropy (rs) of diphenylhexatriene is a biologic/diagnostic marker for Alzheimer's disease (AD), we enrolled 95 clinically diagnosed, probable AD cases from our Alzheimer's Disease Patient Registry and 133 control subjects of similar age and sex randomly selected from the same population base as the cases. We measured rs in platelet membranes following published assay procedures. Laboratory personnel and investigators were blind to the identity of the samples; cases and controls were assayed in random order. Our analyses showed that the distributions of rs values were unimodal and similar for cases and controls. The overall mean differences (control mean-case mean) for the two established assay methods tested were 0.0011 and 0.0003. A nonparametric Wilcoxon rank sum test also showed no difference between cases and controls. Multivariate analysis adjusted for the significant effects of the processing date and analysis platelet recovery led to a final model with the adjusted mean difference of 0.0007 for the principal method. Increased platelet membrane fluidity is not an antemortem diagnostic or biologic marker for AD in our population.

Aged↗