Prediction for unimpaired subjects is different from diagnosis of demented patients.
Explore the source record for details and available documents.
Aged↗
Biomedical subjects
A M Saunders
Publications and source records attributed to A M Saunders.
Apolipoprotein E genotypes in a neuropathological series from the Consortium to Establish a Registry for Alzheimer's Disease.
We evaluated the sensitivity, specificity, and predictive value of the apolipoprotein E (ApoE) epsilon4 allele for the neuropathological diagnosis of Alzheimer disease (AD) in a clinical series of well-characterized AD patients and controls followed longitudinally in the multicenter study of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). In the 162 patients for whom autopsy and ApoE genotype data were available, the clinical diagnosis of AD was verified as the primary cause of dementia in 139 cases (139 of 162, or 86%). The sensitivity and specificity of the epsilon4 allele for AD were both 83%. The positive predictive value of the epsilon4 allele was very high at 97% (115 of 119); whereas, the negative predictive value was 44% (19 of 43), providing no useful information for diagnosis of AD when the epsilon4 allele is not present. Of the cases where AD was not considered the primary or sole cause of dementia (n = 23), 6 cases exhibited concomitant neuropathological findings of definite or probable AD and 2 of these 6 cases had at least one epsilon4 allele. These multicenter data extend previous observations reported from smaller case series of single laboratories and demonstrate that once the clinical diagnosis of AD is established, the presence of an epsilon4 allele reliably predicts the ultimate CERAD neuropathological diagnosis of AD. The findings also suggest that ApoE genotype information is useful clinically in bolstering diagnostic confidence when an epsilon4 allele is present and in identifying a group of patients for whom additional diagnostic evaluations may be warranted when the epsilon4 allele is absent.
Aged↗
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↗
Apolipoprotein E uptake and low-density lipoprotein receptor-related protein expression by the NTera2/D1 cell line: a cell culture model of relevance for late-onset Alzheimer's disease.
Apolipoprotein E has been shown to be a risk factor for late-onset Alzheimer's disease, with the apolipoprotein epsilon 4 allele conferring the risk. Apolipoprotein E is found in neurofibrillary tangles and senile plaques, the pathological characteristics of Alzheimer's disease. To date there is no direct evidence that human neurons can take up exogenous apolipoprotein E, which is necessary if apolipoprotein E is involved in the formation of neurofibrillary tangles. To examine apolipoprotein E uptake we employed the human NTera2/D1 cell line, which can be induced by retinoic acid to differentiate into postmitotic NTera2-N neurons, which have the characteristics and morphology of human central nervous system neurons. We defined the cell line as genotype apolipoprotein epsilon 3/3 and demonstrated that the cells do not synthesize apolipoprotein E but can take up and internalize exogenous recombinant apolipoprotein E3. We also confirmed the expression of the low-density lipoprotein receptor-related protein, a known receptor for apolipoprotein E. The NTera2/D1 cell line therefore provides a useful human cell model for examining the effects of other apolipoprotein E isoforms with a view to defining intraneuronal interactions of apolipoprotein E.
Alzheimer Disease↗
Preliminary report of a genetic basis for cognitive decline after cardiac operations. The Neurologic Outcome Research Group of the Duke Heart Center.
BACKGROUND: Changes in memory and cognition frequently follow cardiac operations. We hypothesized that patients with the apolipoprotein E-epsilon 4 allele are genetically predisposed to cognitive dysfunction after cardiac operations. METHODS: The apolipoprotein E-epsilon 4 allele was evaluated as a predictor variable for postoperative cognitive dysfunction in 65 patients undergoing cardiac bypass grafting at Duke University Medical Center. The primary outcome measure was performance on a cognitive battery administered preoperatively and at 6 weeks postoperatively. RESULTS: In a multivariable logistic regression analysis including apolipoprotein E-epsilon 4, preoperative score, age, and years of education, a significant association was found between apolipoprotein E-epsilon 4 and change in cognitive test score in measures of short-term memory at 6 weeks postoperatively. Patients with lower educational levels were more likely to show a decline in cognitive function associated with the apolipoprotein E-epsilon 4 allele. CONCLUSIONS: This study suggests that apolipoprotein E genotype is related to cognitive dysfunction after cardiopulmonary bypass. Cardiac surgical patients may be susceptible to deterioration after physiologic stress as a result of impaired genetically determined neuronal mechanisms of maintenance and repair.
Age Factors↗
Apolipoprotein E genotyping as a diagnostic adjunct for Alzheimer's disease.
Positive predictive value (PPV) estimates how often a particular test predicts the eventual diagnosis, and it is the basis of any test that attempts to establish a diagnosis. Calculating the PPV depends directly on the entrance criteria for considering the diagnosis and the exit criteria of the generally accepted "gold standard" for establishing the ultimate diagnosis. For a relatively common disease such as AD, the practical usefulness of a diagnostic test also relates to the stage of the disease at which the test can be applied. An accurate and predictive test only has practical value when it can be used early in the course of the disease. Apolipoprotein E (Apo E) is the first genetic locus identified as a susceptibility polymorphism for a common complex disease using positional or candidate cloning strategies. There are three common alleles (epsilon 2 to epsilon 4) and six possible genotypes; about 30% of the population carries an epsilon 4 allele, each additional copy of which is associated with an increased risk of AD and earlier age of onset distribution. In patients with cognitive impairment of the Alzheimer type, who have been diagnosed with possible or probable AD, the presence of an Apo E-epsilon 4 allele is likely in more than 50% of patients for whom the PPV is greater than 97%. Apo E genotyping is the only diagnostic adjunct that has been subjected to rigorous measurements of specificity, sensitivity, PPV, and NPV. In the past, testing of dementia patients was directed at "ruling out" other treatable causes. Results from the initial studies of the PPV of Apo E genotyping for AD showed that the PPV of Apo E genotyping was greater than 97%. The paradigm for AD diagnosis is changing. Apo E genotyping can provide useful diagnostic information and that accuracy will improve as other susceptibility genetic risk factors are identified.
Aged↗
Clinical overdiagnosis of vascular dementia versus necropsy confirmed series.
Explore the source record for details and available documents.
Alzheimer Disease↗
Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype.
To determine whether apolipoprotein E epsilon 2 (APOE-epsilon 2) affects neuropathology in aging and Alzheimer's disease (AD), we compared beta-amyloid plaque (A beta P) and neurofibrillary tangle densities, neuropil thread formation, and amyloid angiopathy in five APOE-epsilon 2/3 AD patients, five APOE-epsilon 3/3 AD patients, five APOE-epsilon control patients, and five APOE-epsilon 3/3 control patients. We examined the (frontal and parietal) neocortex, hippocampus, entorhinal cortex, and cerebellum and found A beta P densities to be lower (t = 3.121, p = 0.011) in the cortex of APOE-epsilon 2/3 AD patients than in APOE-epsilon 3/3 AD patients. Amyloid angiopathy was also less in APOE-epsilon 2/3 patients than in APOE-3/3 patients (U = 4.500, p = 0.027). Control APOE-epsilon 2/3 brains had little AD-related pathology; even our 102-year-old control case showed few A beta Ps compared with the elderly APOE-epsilon 3/3 cases. The APOE-epsilon 2/3 genotype may influence pathologic phenotype in some aged normal and AD populations.
Aged↗
Apolipoprotein E epsilon 4 allele and hippocampal volume in twins with normal cognition.
We examined the relation of APOE-epsilon 4, hippocampal volume, and cognitive performance in ten pairs of cognitively normal twins who had a mean age of 62.5 years (SD = 7.8). There were no significant differences in neuropsychological measures of the groups categorized by the presence of an epsilon 4 allele. However, the mean normalized right and left hippocampal volumes were smaller in the epsilon 4 groups compared to the group without epsilon 4. Combined with prior reports, these findings suggest that epsilon 4 is associated with differences in brain morphology that may be evident when no symptoms of dementia are present.
Alleles↗
Evaluation of suspected dementia.
Explore the source record for details and available documents.
Apolipoproteins E↗
No association between alpha 1-antichymotrypsin and familial Alzheimer's disease.
Alzheimer's disease (AD) is the most common mid to late age-of-onset neurodegenerative disorder. AD has a strong and complex genetic etiology, and multiple genes, acting independently and/or interacting, likely affect the risk of developing AD. Several genes involved with AD already have been described, but only the APOE gene on chromosome 19q has been shown to affect the risk of the most common form of AD, occurring with onset over the age of 65. Because a substantial portion of late-onset AD is not explained by APOE, other genes affecting late-onset AD likely occur. These could act either independently or perhaps interact with APOE. alpha 1-Antichymotrypsin (ACT) is a major component of the amyloid plaques found in the brains of AD patients and may play a role in the pathophysiology of AD. It has been proposed that a specific polymorphism within the ACT gene interacts with APOE to increase the risk of developing AD. Our results do not confirm this finding.
Adult↗
Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging.
New treatments for Alzheimer's disease (AD) are more likely to slow or halt disease progression rather than to reverse existing neuronal damage. Identifying persons with mild cognitive complaints who are at risk for AD will allow investigators to apply anti-dementia treatments before extensive brain damage develops. The discovery of the apolipoprotein E epsilon 4 allele (APOE epsilon 4) as a major risk factor for AD offers promise of assisting in early detection and prediction of Alzheimer's disease, particularly when genetic assessments are combined with other biomarkers such as neuroimaging. Studies of relatives at risk for familial AD using neuroimaging (positron emission tomography [PET]) and genetic assessments of APOE suggest that at-risk relatives with APOE epsilon 4 have lower parietal metabolism than those without APOE epsilon 4. Additional techniques that might increase sensitivity and specificity include longitudinal assessment of clinical and brain functional change, pharmacological challenges of short-acting anticholinergic agents, and memory activation paradigms during functional scanning. Such strategies should eventually assist in early detection of AD and in vivo therapeutic monitoring of brain function during experimental anti-dementia treatment trials.
Adult↗
Specificity, sensitivity, and predictive value of apolipoprotein-E genotyping for sporadic Alzheimer's disease.
BACKGROUND: We aimed to determine the specificity, sensitivity, and predictive value of apolipoprotein E (APOE) genotyping in 67 consecutive patients with clinical diagnoses of sporadic Alzheimer's disease (AD) who underwent necropsy. METHODS: We studied patients who attended the Duke Memory Disorders Clinic and were diagnosed as having probable AD. These patients were followed up until they died. APOE genotyping was done during life in most cases, but in some brain tissue obtained at necropsy was used. Members of known AD families were excluded. FINDINGS: After neuropathological examination 57 (85%) of 67 of our patients were confirmed as having AD including all 43 who had at least one APOE-epsilon 4 allele. None of the patients found not to have AD carried an epsilon 4 allele. In this series, the specificity of the epsilon 4 allele was 100%, the sensitivity 75%, the positive predictive value 100%, and the negative predictive value 42%. In this necropsy-confirmed series, the epsilon 4/epsilon 4 genotype predicted AD with 100% accuracy. The epsilon 3/epsilon 4 and epsilon 2/epsilon 4 genotypes were also unexpectedly highly specific for AD. INTERPRETATION: Data from hundreds of necropsy-confirmed non-AD patients in other longitudinal necropsy series will allow the predictive value of APOE genotypes to be assessed with useful confidence limits.
Alleles↗
No association between very low density lipoprotein receptor (VLDL-R) and Alzheimer disease in American Caucasians.
The very low density lipoprotein receptor gene (VLDL-R) is a receptor for apolipoprotein-epsilon (APOE)-containing lipoproteins, and thus has been suggested as a possible risk factor for Alzheimer disease (AD). Recently, Okuizumi et al. [Nature Genet, II (1995) 207-209] reported an association between the 96 bp allele at the VLDL-R locus and AD in a Japanese population. The association resulted in a two-fold increase of risk that decreased with increasing age. We have examined this association in 316 Caucasian sporadic AD patients, comparing their findings to 160 Caucasian AD spouse controls. We also investigated 53 late-onset Caucasian AD families for association and linkage. Our data failed to confirm linkage and/or association to the VLDL-R locus. Stratification by age at onset or APOE genotype also failed to show significant results.
Adult↗
No genetic effect of alpha1-antichymotrypsin in Alzheimer disease.
Alzheimer disease (AD) is the most common neurodegenerative disorder for individuals over the age of 40. AD has a complex etiology, and it is likely that multiple genes, acting independently and/or interacting, affect the risk of developing AD. Several genes involved with AD have been described already, but only the APOE gene on chromosome 19q has been shown to affect the risk of the common late onset form of AD. alpha1-Antichymotrypsin (AACT) is a major component of the amyloid plaques found in the brains of AD patients, and an allele in its gene has been proposed to increase the risk of developing AD when also associated with the APOE-4 allele. We have examined the role of this AACT polymorphism in a large set of families and sporadic cases, and do not see any effect, either alone or in combination with the APOE-4 allele.
Alzheimer Disease↗
Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism.
There are two distinct viewpoints on the association of the inheritance of apolipoprotein E (APOE) alleles and the age of onset distribution of Alzheimer's disease (AD): genetic and phenotypic expression. There have been multiple corroborations of the APOE-epsilon 4 association with Alzheimer's disease in populations around the world in clinic based studies as well as emerging epidemiological studies. The genetic data do not imply mechanism of pathogenesis. The phenotypic expression of AD has been based in theories based on amyloid plaques or neurofibrillary tangles. ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner. The interaction with tau had been thought to be an in vitro artifact, since apoE had not been previously localized to the neuronal cytoplasm. Immuno-EM studies have localized apoE in neuronal cytoplasm. ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain under conditions in which apoE4 is less tightly bound. These data further support a hypothesis that apoE3 (and apoE2) protect the microtubule binding domain of tau from binding to itself to form paired helical filaments and neurofibrillary tangles, while protecting the site for microtubule stabilizing interactions with beta-tubulin. These data are supported by recent data from APOE knock-out mice demonstrating dendritic alterations leading to synaptic simplification similar to that observed in AD.
Age of Onset↗
Alzheimer's disease and apolipoprotein E-4 allele in an Amish population.
Alzheimer's Disease (AD) is a complex genetic disorder with four loci already identified. Mutations in three of these, the amyloid precursor protein, presenilin I, and presenilin II, cause early-onset AD. The apolipoprotein E (APOE) gene contributes primarily to late-onset AD. The APOE-4 allele acts in a dose-related fashion to increase risk and decrease the age-of-onset distribution in AD. We examined the effect of APOE on AD in a previously unstudied Amish population that has a lower prevalence of dementia compared with other populations. We sampled a large inbred family with 6 late-onset AD members. We also genotyped 53 individuals from the general Amish population as controls for the APOE allele frequency estimates. The frequency of the APOE-4 allele in the Amish controls was 0.037 +/- 0.02. This differed significantly compared with three independent sets of non-Amish white controls (p < 2 x 10(-4), p < 6 x 10(-5), and p < 2 x 10(-6)). In addition, all Amish AD-affected individuals had APOE 3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the lower frequency of dementia in the Amish may be partially explained by the decreased frequency of the APOE-4 allele in this population, and that the inbred nature of this pedigree, with its strong clustering of cases contrasted against the lower frequency of dementia, indicates that additional genetic factors influence late-onset AD.
Adult↗
Lack of association of very low density lipoprotein receptor gene polymorphism with Caucasian Alzheimer's disease.
To determine whether the association of the very low density lipoprotein receptor (VLDL-R) gene with Alzheimer's disease (AD), which has recently been identified in Japanese AD patients, is commonly observed in AD patients of other ethnic backgrounds, we have investigated the allele frequency of the polymorphic CGG repeat in the 5'-UTR of the VLDL-R gene using a data set of 84 Caucasian AD patients with 104 Caucasian controls. Although the allele frequency of the 8-repeat allele was slightly lower, and that of 9-repeat allele was slightly higher, in the Caucasian AD patients than in Caucasian controls, the differences were not statistically significant. Multiple logistic regression analysis using apolipoprotein E4 (APOE4) allele, 5, 8-, or 9-repeat allele of the VLDL-R gene, sex, and age at onset as the predictors revealed that only the APOE4 allele was significantly associated with AD in the data set of the Caucasian AD patients and controls.
Aged↗