Lack of association between the apolipoprotein E epsilon4 allele (APOE epsilon4) and chronic schizophrenia.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
F Crawford
Publications and source records attributed to F Crawford.
Superoxide free radical and intracellular calcium mediate A beta(1-42) induced endothelial toxicity.
The 39-42 amino acid residue amyloid beta peptide (A beta), the major protein component in senile plaques and cerebrovascular amyloidosis in the brain in Alzheimer's disease (AD), has been shown to be neurotoxic in vitro. Accumulating data from several areas suggest that cerebrovascular dysfunction and damage may also play a significant role in the AD process. For instance, we have recently demonstrated enhanced vasoconstriction and resistance to relaxation in intact rat aorta treated with A beta [Thomas et al., beta-Amyloid-mediated vasoactivity and vascular endothelial damage, Nature, 380 (1996) 168-171]. Significant vessel damage occurred after thirty minutes of exposure, but could be prevented with superoxide dismutase. To further investigate the role of A beta toxicity on endothelial cells, we have applied A beta peptides to cultures of human aortic endothelial cells (HAEC). Our results show that both A beta(1-42) and A beta(25-35) are toxic to HAEC in a time- and dose-dependent manner, and that this toxicity can be partially prevented by the calcium channel blocker, verapamil, and the antioxidant, superoxide dismutase. The common form of A beta, A beta(1-40), which has been shown to be neurotoxic, is much less toxic to HAEC. A beta toxicity to HAEC occurs within 30 min of treatment with relatively lower doses than those usually observed in primary cultured neurons and vascular smooth muscle cells. It was recently reported that a variety of mutations in the beta-amyloid protein precursor gene and the Presenilin-1 and -2 genes linked to early-onset familial AD cause an increase in the plasma concentration of A beta(1-42) in mutation carriers [Scheuner et al., Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vitro by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Med., 2 (1996) 864-870]. Human aortic endothelial cells are more sensitive to A beta(1-42) than A beta(1-40), via a pathway involving an excess of superoxide free radicals and influx of extracellular calcium. Finally, we have evidence that both apoptotic and necrotic processes are activated by the A beta peptides in these endothelial cells.
Amyloid beta-Peptides↗
No interaction between the APOE and the alpha-1-antichymotrypsin genes on risk for Alzheimer's disease.
It is now known that possession of one of the three common forms of the apolipoprotein E gene (allele epsilon 4) confers an increased risk for Alzheimer's disease (AD), both familial and sporadic, and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of, or interaction with, the existing apolipoprotein E (APOE) risk, are now under investigation including the alpha-1-antichymotrypsin (ACT) gene, the very low density lipoprotein receptor (VLDL-R) gene, and the presenilin-1 (PS-1) gene. Kamboh et al. [1995] reported that a polymorphism in the alpha-1-antichymotrypsin gene could modify the risk for AD conferred by the APOE locus, specifically by increasing the risk for AD among epsilon 4 homozygotes. The ACT gene, which is found on chromosome 14, has previously been proposed as a candidate for AD due to the presence of the ACT protein in senile plaques and the reported elevation of the protein in the cerebro-spinal fluid (CSF) and serum of AD cases. We have investigated this reported association within our familial and sporadic AD dataset, where we find no independent association between ACT and the occurrence of AD. Logistic regression analysis excludes ACT or the interaction between ACT and APOE as significant contributors in the prediction of disease status. By this analysis, ACT genotyping does not provide additional information about an individual's risk of Alzheimer's disease beyond the risk information conferred by APOE genotype alone.
Aged↗
No association between the intronic presenilin-1 polymorphism and Alzheimer's disease in clinic and population-based samples.
Mutations in the Presenilin 1 (PS1) gene on chromosome 14 cause most early-onset familial Alzheimer's disease (AD). An intronic polymorphism in the PS1 gene was recently identified and reported to be associated with late-onset AD [Wragg et al., Lancet 347: 509-512, 1996]. The authors found an excess of homozygotes for the more common allele (allele 1) in AD cases, associated with an approximate doubling of risk. In the present study, we report the PS1 polymorphism distributions in clinic and population-based samples. We were not able to replicate the findings of Wragg et al. [1996]. Our results are consistent with those of other researchers and do not support the conclusion that the PS1 polymorphism is associated with late-onset AD.
Alleles↗
No association between the very low density lipoprotein receptor gene and late-onset Alzheimer's disease nor interaction with the apolipoprotein E gene in population-based and clinic samples.
It is now commonly known that possession of one of the three common alleles of the apolipoprotein E (APOE) gene (allele epsilon 4) confers an increased risk for both familial and sporadic Alzheimer's disease (AD), and that this risk is dose-dependent. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, are under investigation. One such gene, the very low density lipoprotein receptor (VLDL-R) gene, was reported by Okuizumi et al. to be independently associated with AD in a Japanese population, but not interactive with the APOE4 conferred risk. Their clinic-based data set demonstrated a 2-fold increased risk conferred by the 5-repeat allele of a polymorphism in VLDL-R. As recruitment from a clinic rather than a population-based sample may result in a distortion of allele frequencies, as has been shown with APOE allele frequencies, it is important to investigate this association in a population-based study. We have genotyped both population and clinic-based AD data sets at this VLDL-R polymorphism, and we find no independent association between the VLDL-R gene and the occurrence of AD in either sample. Further, despite the biochemical relationship between the VLDL-R and APOE proteins, we find no significant statistical interaction between the alleles at these loci.
Age of Onset↗
Familial and population-based studies of apolipoprotein E and Alzheimer's disease.
The finding of an association between the epsilon 4 allele of the APOE locus and the early expression of late-onset Alzheimer's disease (AD) is robust. However, the estimates of the proportion of AD cases carrying one or more copies of the epsilon 4 allele vary dramatically between studies (highest estimates being 180% of lowest ones). Here we compare the results of association studies in samples drawn from an epidemiologically based study design and samples drawn from families selected for linkage studies. The significant differences between results probably point to the unwitting selection of familial factors other than the APOE locus in the family history positive samples. We conclude that any selection procedure tending to enrich samples for positive family history will also tend to artificially increase APOE epsilon 4 allele frequencies in probands. This is of significance in samples drawn from clinical settings where referral may be influenced by previous known family history. Further work is needed to clarify the nature of the additional factors operating within families. We also report data showing an association between late-onset AD and a polymorphism in an adjacent locus to APOE-the APOCI locus. As no additional risk for AD can be attributed to the APOCI locus, the most likely explanation for the association between AD and APOCI is the disequilibrium between the APOCI and APOE loci. Therefore, there are likely to be other genetic markers in the area that can be used in the same way as APOE as a marker of risk for the disease.
Age of Onset↗
Dopamine DRD2/Cys311 is not associated with chronic schizophrenia.
A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia.
Asian People↗
How effective is therapeutic ultrasound in the treatment of heel pain?
OBJECTIVES: To evaluate the therapeutic effect from ultrasound in the treatment of plantar heel pain by physiotherapists and podiatrists, and to quantify the placebo effect of this electrophysical agent. METHODS: Patients experiencing episodes of plantar heel pain were allocated randomly, at each episode, to receive either true ultrasound (machine calibrated to deliver a dose of ultrasound at 0.5 w/cm2, 3 MHz, pulsed 1:4), for eight minutes, or sham ultrasound (only the timer on the machine activated). Each episode was treated, according to randomisation, eight times. An independent observer set the equipment before obscuring the control panel with a drape. All treatments were undertaken by the same operator. Patients' pain scores were measured on a 10 cm linear analogue scale before the course of eight treatments commenced and at the end of the course, and analysed using a Wilcoxon Signed-Ranks test. RESULTS: Nineteen patients experienced episodes of heel pain (seven bilateral). Both groups showed a reduction in pain; the improvement was 30% in the treated group and 25% in the placebo group (p = 0.5). CONCLUSIONS: Therapeutic ultrasound at a dosage of 0.5 w/cm2, 3 MHz, pulsed 1:4, for eight minutes is no more effective than placebo in the treatment of plantar heel pain.
Chronic Disease↗
Occurrence of the Cys311 DRD2 variant in a pedigree multiply affected with panic disorder.
Following the detection of the rare DRD2 codon 311 variant (Ser-->Cys) in an affected member from a large, multiply affected panic disorder family, we investigated the occurrence of this variant in other family members. The variant occurred in both affected and unaffected individuals. Further screening in panic disorder sib pairs unrelated to this family failed to detect the Cys311 variant. Our data suggests that this variant has no pathogenic role in panic disorder.
Base Sequence↗
Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's Disease but is not causative.
An association has been observed in several independent data sets between late onset Alzheimer's Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the epsilon 4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD.
Age Factors↗
Association of apolipoprotein E but not B with Alzheimer's disease.
In our studies apolipoprotein E4 (APOE4) is associated with both early- and late-onset Alzheimer's disease. Alzheimer's patients from West Texas were screened for the APOE4 allele, which was found at frequencies of 0.43 and 0.59 in familial late- and early-onset cases. Sporadic cases had lower frequencies, but they still were 2-4 times higher than control spouses. To determine whether the APOE association may be a risk factor for coronary disease as well, we examined two APOB gene restriction sites that have previously been found to be associated with coronary artery disease, especially myocardial infarctions. The APOB alleles were found at similar frequencies in Alzheimer's patients and control spouses.
Aged↗
Technical feasibility of genetic testing for Alzheimer's disease.
This article examines the feasibility of using molecular genetic information for diagnostic and predictive testing in Alzheimer's disease (AD). The scope is limited largely to early onset familial cases, but a brief update on genetic research in late onset disease is included. The usefulness and accuracy of such testing is determined by the results and interpretation of current research data which are presented herein. The ethical and legal issues implicated in such procedures are not covered but are examined elsewhere in this issue. During the course of the genetic analysis of AD, it has become clear that it is an etiologically heterogeneous disorder. In understanding the genetic predisposition to AD there should be continual attention to this message. Age of onset and familiality have emerged as the most useful clinical features demarcating subgroups with common origins. At least two genes predispose (independently) to early onset familial AD: the beta-amyloid precursor protein gene (beta APP) and an unidentified gene on chromosome 14. Germ line mutations in these genes act dominantly. The accurate use of genetic data in AD, for diagnostic, screening and predictive purposes relies on the most up-to-date knowledge of the transmission of the disorder in relation to mutations in these genes. The interpretation of genetic data is examined for each of the known early onset genes. In addition, we review the data pertaining to late onset disease and risk conferred by the APOE locus to both familial and nonfamilial cases. The use of these data in genetic risk analysis must be reserved until a full explanation of the association and its meaning is forthcoming. Isolated cases of AD occur at all ages of onset, but no AD mutations in the beta APP gene have yet been identified in isolated cases.
Adult↗
Age of onset in familial early onset Alzheimer's disease correlates with genetic aetiology.
Age of onset is the most robust clinical feature demarcating aetiologic subtypes of familial Alzheimer's disease. It has previously been noted that early onset disease (arbitrarily below the age of 65 years) conforms to an autosomal dominant pattern of transmission. Late onset disease is generally thought to have a more complex aetiology. We present data here suggesting that early onset disease can be subdivided by genetic aetiology with which age of onset correlates. In general, those pedigrees showing linkage to the chromosome 14 locus have a mean age of onset in the forties whereas those pedigrees with an APP mutation have an age of onset in the fifties.
Adult↗
Screening for the APP codon 670/671 mutations in Alzheimer's disease.
A mutation at codons 670 and 671 of exon 16 of the amyloid precursor protein has recently been identified as a cause of early onset familial Alzheimer's disease. Using restriction enzyme digestion, screening failed to reveal the occurrence of this mutation in 43 families with early onset, 31 families with late onset, 30 cases of sporadic Alzheimer's disease or 30 clinically normal individuals.
Adult↗
Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene reveals the beta-amyloid sequence to be normal in cases of the parkinson dementia complex of Guam.
Exons 16 and 17 of the beta-amyloid precursor protein gene has been sequenced in individuals with the amyotropic lateral sclerosis/Parkinson's dementia complex of Guam to test the hypothesis that this disease is an allelic variant of Alzheimer's disease and to test whether sequence differences within beta-amyloid in this population contributes to the non-deposition of this peptide in the disorder. The sequence was normal.
Aged↗
Genetic and molecular advances in Alzheimer's disease.
The abnormal deposition of amyloid beta protein (A beta) in the brain is the major neuropathological characteristic of Alzheimer's disease (AD). The disease in some early-onset familial cases develops as a result of mutations in the gene coding for the beta-amyloid precursor protein (beta APP) and in the majority of the rest appears to be caused by an unidentified gene on chromosome 14. Only one of the beta APP gene mutations has been associated with aberrant beta APP processing, resulting in an excess production of A beta in vitro, a result suggesting that there might be excessive A beta cleavage from beta APP in AD in vivo. By contrast with the beta APP mutants, no particular allele of the apolipoprotein E (APOE) gene predicts the disease completely but one allele is associated with the disease suggesting APOE is a risk locus for AD. This discovery has been linked to increased deposition of A beta in those cases carrying the risk allele. However, the genetic evidence is currently not sufficient to indicate whether beta APP mismetabolism, direct or indirect A beta neurotoxicity or dysfunction of beta APP (or its derivatives) are central to the AD process.
Age of Onset↗
Improved direct sequencing of Alzheimer's amyloid precursor protein (APP) exons 16 and 17.
Direct sequencing of exon 17 of the amyloid precursor protein (APP) gene led to the identification of 3 different types of APP717 pathogenic mutations associated with familial Alzheimer's disease (FAD). The low frequency of these mutations results in having to screen many samples in order to identify new families affected by them, which is laborious and time consuming. Thus, in order to help the identification of these mutations in additional countries and to search for new mutations in APP, perhaps in other exons also causing FAD, we have optimized the procedure and reduced the time necessary for sample preparation from 11 h to 3 1/2 h.
Alzheimer Disease↗
Alzheimer's--a correction.
Explore the source record for details and available documents.
Alzheimer Disease↗