Epsilon4 Allele Of Apolipoprotein Research Articles

Ranking the risk factors for Alzheimer's disease; findings from the UK Biobank study.

The cause of the most common form of dementia, sporadic Alzheimer's disease (AD), remains unknown. This may reflect insufficiently powered studies to date for this multi-factorial disorder. The UK Biobank dataset presents a unique opportunity to rank known risk factors and determine novel variables. A custom machine learning approach for high dimensionality data was applied to explore prospectively associations between AD in a sub-cohort of 156,209 UK Biobank participants aged 60-70 including more than 2,090 who were subsequently diagnosed with AD. After the possession of the APOE4 allele, the next highest ranked risk factors were other genetic variants within the TOMM40-APOE-APOC1 locus. When stratified by their apolipoprotein 4 (APOE4) carrier status, the most prominent risk factors in carriers were AST:ALT ratio, the "number of treatments/ medications" taken as well as "time spent in hospital" while protection was conferred by "Sleeplessness/Insomnia". In non-APOE carriers, lower socioeconomic status and fewer years of education were highly ranked but effect sizes were small relative to APOE4 carriers. Possession of the APOE4 allele was confirmed as the most important risk factor in AD. Other TOMM40-APOE-APOC1 locus variants further moderate the risk of AD in APOE4 carriers. Liver pathology is a novel risk factor in APOE4 carriers while "Sleeplessness/Insomnia" is protective in AD irrespective of APOE4 status. Other factors such as "Number of treatments/ medications" suggest that multimorbidity is an important risk factor for AD. Future treatments aimed at co-morbidities, including liver disease, may concomitantly lower the risk of sporadic AD.

Correlations between APOE4 allele and regional amyloid and tau burdens in cognitively normal older individuals

The correlations between apolipoprotein epsilon 4 (APOE4) status and regional amyloid, tau, and cortical thickness in cognitively normal elderly are not fully understood. Our cross-sectional study aimed to compare regional amyloid/tau burden, and cortical thickness according to APOE4 carrier status and assess correlations between APOE4 and Alzheimer’s disease (AD)-related biomarker burdens. We analyzed 185 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Participants aged 55–90 with normal cognitive function were divided into amyloid ß-positive (Aß+) APOE4 carriers (group 1, n = 27), Aß+ APOE4 non-carriers (group 2, n = 29), and Aß− normal controls (group 0, n = 129). We compared amyloid depositions, tau depositions, and cortical thickness among the three groups and assessed correlations between APOE4 existence and imaging biomarkers adjusted for age and sex. The participants in group 2 were older than those in the other groups. The regional amyloid/tau standardized uptake value ratios (SUVRs) did not differ between groups 1 and 2, but the amyloid/tau SUVRs in most regions were numerically higher after adjusting for age difference. APOE4 allele had robust correlations with increased amyloid burden in the fronto-temporo-parietal cortical areas after adjustment for age and sex, but it had weaker and mixed correlations with the regional tau burden and did not have significant correlation with cortical thickness. We identified that the presence of APOE4 allele might be more highly associated with amyloid deposition than with other AD-related biomarkers such as tau or cortical thickness in cognitively normal elderly.

Causal inference for semi-competing risks data.

The causal effects of Apolipoprotein E $\epsilon4$ allele (APOE) on late-onset Alzheimer's disease (AD) and death are complicated to define because AD may occur under one intervention but not under the other, and because AD occurrence may affect age of death. In this article, this dual outcome scenario is studied using the semi-competing risks framework for time-to-event data. Two event times are of interest: a nonterminal event time (age at AD diagnosis), and a terminal event time (age at death). AD diagnosis time is observed only if it precedes death, which may occur before or after AD. We propose new estimands for capturing the causal effect of APOE on AD and death. Our proposal is based on a stratification of the population with respect to the order of the two events. We present a novel assumption utilizing the time-to-event nature of the data, which is more flexible than the often-invoked monotonicity assumption. We derive results on partial identifiability, suggest a sensitivity analysis approach, and give conditions under which full identification is possible. Finally, we present and implement nonparametric and semiparametric estimation methods under right-censored semi-competing risks data for studying the complex effect of APOE on AD and death.

Effects of LDL Cholesterol and Statin Use on Verbal Learning and Memory in Older Adults at Genetic Risk for Alzheimer's Disease.

The apolipoprotein epsilon 4 (APOE4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning. This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD. Neuropsychological, LDL, statin use, and APOE4 data were extracted from an ongoing longitudinal study at the Banner Alzheimer's Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47-75, with a family history of probable AD in at least one first-degree relative. In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers. LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status.

The beginnings of Alzheimer’s disease: A review on inflammatory, mitochondrial, genetic and epigenetic pathways

Alzheimer?s Disease (AD) is the most common cause of sporadic dementia, as it affects 60% of cognitive impaired patients; it commonly affects middle and late life, and it is considered an age-related disease. Early-onset familial AD is associated with mutations of the genes encoding amyloid precursor protein (APP), presenilin 1 (PS-1), or PS-2, resulting in the overproduction of amyloid beta-protein. Epidemiological and case-control studies have led to the identification of several risk factors for sporadic AD. The most concrete genetic risk factor for AD is the epsilon4 allele of apolipoprotein E gene (APOE). In addition, several genes such as CTNNA3, GAB2, PVRL2, TOMM40, and APOC1 are known to be the risk factors that contribute to AD pathogenesis. A direct role of interaction between genetic and environmental determinants has been proposed in an epigenetic dynamic for environmental factors operating during the preconceptual, fetal and infant phases of life. Also the the association between mtDNA inherited variants and multifactorial diseases and AD has been investigated by a number of studies that, however, didn?t reach a general consensus on the correlation between mtDNA haplogroups and AD.

Inverse effect of the APOE epsilon4 allele in late- and early-onset Alzheimer's disease.

In Alzheimer's disease patients (AD), the age at onset (AAO) ranges from 40 to 90. Usually, AD patients who develop symptoms before the age of 65 are classified as early onset(EO). The best known genetic risk factor for AD is the ε4 allele of the apolipoprotein E (APOE). In this study, 474 subjects with AD were consecutively recruited in the memory clinic of the Santa Lucia Foundation in Rome. The best fitting model for the discrimination between EO and late onset (LO) was chosen based on lowest value of the Bayesian Information Criterion, which suggests the theoretical model with minimal deviation from the empirical distribution function of AAO in our sample. The FMM was used to compare EO and LO groups with respect to the following demographic and clinical variables: gender, age, education, MMSE and NPI. Furthermore a quantitative assessment of ADL and IADL was performed. Finally, the frequency of the APOE ε4 allele was compared in EO and LO groups. Using the admixture analysis, we established that the AAO discriminating EO from LO-AD was 63-64. Higher education was associated with earlier onset in the EO but not in LO, and duration of illness was associated with earlier onset only in LO. The ε4 allele was associated with later onset in EO but earlier onset in LO. Finally, increased impairment in ADL, IADL and NPI was associated with later onset only in the LO subgroup. Thus, the ε4 allele of the APOE gene was significantly associated with both EO and LO distributions but with opposite effect, suggesting genetic heterogeneity. Additional studies are needed to further clarify the genetic mechanisms differentiating EO- and LO-AD.

Apolipoprotein epsilon 4 genotype is associated with less improvement in cognitive function five years after cardiac surgery: a retrospective cohort study.

Cognitive performance after cardiac surgery can be impaired, and genetic risk factors have previously been suggested. When compared with other isoforms of the gene, the apolipoprotein epsilon 4 (APOE4) allele is associated with worse outcomes in many neurologic disorders. We hypothesized that the APOE4 allele is associated with less favourable cognitive function five years after surgery. Caucasian patients enrolled in previously reported prospective cognitive trials in both cardiac and non-cardiac surgery participated in this retrospective cohort study. Neuropsychological function was assessed at baseline and five years postoperatively. The relationship between change in cognitive index score and APOE was evaluated using multivariable linear regression. An additive genetic model toward the epsilon 4 allele was applied with adjustment for baseline cognition, years of education, age, presence of diabetes in both cohorts, and presence of coronary artery disease in the non-cardiac surgery cohort. A total of 357 patients were included in this study. In the cardiac surgery group (n=233), baseline cognitive index (P<0.001), years of education (P=0.04), age at time of surgery (P<0.001), and the APOE4 allele (P=0.009), were associated with a five-year change in cognitive index. Patients carrying the APOE4 allele showed less improvement in cognitive index scores five years after cardiac surgery compared with patients without the APOE4 allele. In the non-cardiac surgery (n=124) group, no association was found between APOE4 allele status and change in cognitive index. We report an association between APOE4 and neurocognitive function five years following cardiac surgery. Preoperative identification of patients with the APOE4 genotype may improve stratification of cardiac surgery patients at risk for a less favourable cognitive trajectory.

BRAIN RESERVE IS AS IMPORTANT AS ALZHEIMER'S AND VASCULAR PATHOLOGY IN DETERMINING DEMENTIA STATUS: THE NUN STUDY

Although Alzheimer and vascular pathology are known to be strong determinants of dementia, the relative importance of brain reserve (brain volume and education) in affecting dementia status is unknown. Using data from the Nun Study, we calculated etiologic fractions for predictors of dementia at death. Predictors were determined from a factor analysis of known risk factors including educational attainment, presence of one or more apolipoprotein E-epsilon4 alleles, as well as mean densities of neurofibrillary tangles and neuritic plaques in the neocortex, presence of lacunar and large infarcts, rating of arteriosclerosis in the circle of Willis, and brain weight (excluding meninges) determined at autopsy. Three factors with Eigenvalues from 1.24-1.73 were identified [loadings indicated by L]: (1) Alzheimer's pathology (tangle [L= .82] and plaque counts [L=.75 ], and APOE4 [L=.65]); vascular pathology (atherosclerosis [L=.60], lacunar [L=.78] and large infarcts [L=.70]); and reserve (education [L=.79], brain weight [L=.73]). Factor scores were calculated and dichotomized at the median to yield high and low values for each factor. Etiologic fractions (fraction of cases attributable to each of the risk factors) for high Alzheimer, high vascular and low reserve were 38.5%, 25.6% and 39.7%, respectively. In other analyses, we found that brain weight at autopsy was most strongly related to head circumference (p<0.0001) rather than to Alzheimer (p=0.01) or vascular (p=0.67) pathology, suggesting that early brain growth plays a more important role in determining brain weight at death than brain pathology. Brain reserve plays a very strong role in determining dementia status at death, on a par with Alzheimer pathology. Higher reserve may help to explain the absence of dementia in about a third of individuals fulfilling Reagan criteria for neuropathological AD. Models predicting lifetime risk of AD need to take into account reserve and vascular lesions in addition to beta amyloid load. The findings suggest that interventions that facilitate brain growth may be very effective in preventing dementia.

Prognostic Value of Apolipoprotein E Epsilon4 Allele in Patients with Traumatic Brain Injury: A Meta-Analysis and Meta-Regression

Current scientific evidence suggests that the apolipoprotein E epsilon4 (APOE4) allele may be associated with a good prognosis for patients with traumatic brain injury (TBI); however, many existing studies have yielded inconclusive results. This meta-analysis aims to obtain a more precise estimation of the association between APOE4 allele and prognosis of TBI patients. A literature search of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CNKI and CBM databases was conducted for articles published before July 1st, 2013. Crude odds ratios (OR) with 95% confidence intervals (CI) were calculated. Thirteen cohort studies were included with a total of 662 TBI patients with APOE4 (+) and 1614 TBI patients with APOE4 (-). The meta-analysis results revealed that the APOE4 allele was associated with a poor prognosis in TBI patients (OR=0.68, 95% CI: 0.48-0.96, p=0.027). Subgroup analysis by ethnicity indicated that TBI patients with APOE4 (+) had a worse prognosis than those with APOE4 (-) in Asian populations (OR=0.46, 95% CI: 0.21-0.99, p=0.046), but not in Caucasian populations (OR=0.75, 95% CI: 0.53-1.08, p=0.120). A further subgroup analysis by TBI grade showed that the APOE4 allele was associated with poor prognosis in severe TBI patients (OR=0.43, 95% CI: 0.21-0.87, p=0.020). However, there was no evidence for any association between the APOE4 allele and poor prognosis in patients with other grades of TBI (all p>0.05). The current meta-analysis indicates that the APOE4 allele may be associated with a poor prognosis in severe TBI patients and in Asian populations. The APOE4 allele may be used as a biomarker in predicting the prognosis of TBI patients.

Physical activity and brain function in older adults at increased risk for Alzheimer's disease.

Leisure-time physical activity (PA) and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4) allele, diagnosis of mild cognitive impairment (MCI), or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD.

Resting-State Network Disruption and APOE Genotype in Alzheimer's Disease: A lagged Functional Connectivity Study

BackgroundThe apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”.Methodology/Principal FindingsResting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions.Conclusions/SignificanceIn addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.

Regional cerebral perfusion in patients with Alzheimer’s disease and mild cognitive impairment: effect of APOE Epsilon4 allele

The objective of this study was to evaluate the effect of apolipoprotein E (APOE) epsilon 4 allele on regional cerebral perfusion (rCBF) changes using arterial spin labeling (ASL) magnetic resonance imaging (MRI) in subjects who are carriers or noncarriers of this risk factor for Alzheimer disease (AD). Twenty-five subjects with AD, 25 with amnestic mild cognitive impairment (MCI) and 25 cognitively normal (CN) subjects underwent isotropic volumetric T1-weighted imaging and pulsed ASL MRI. All subjects were divided into carrier or noncarriers of the epsilon4 allele. Voxel-based statistical analyses were performed among groups on rCBF by ANOVA tests. In each subject group, we also evaluated the rCBF change between carrier and noncarrier groups. rCBF was significantly reduced in AD subjects compared to other subjects. In CN and AD subjects, rCBF in the carrier group was significantly reduced in several areas of the brain compared with that of the noncarrier group. In the carrier group, rCBF was significantly increased in the right parahippocampal gyrus, the bilateral cingulate gyri and the right posterior cingulate on the MCI group in addition to the right superior frontal gyrus in the AD group. rCBF in the CN and AD groups were significantly reduced in the subjects with the carriers of the epsilon4 allele, which is a risk factor for Alzheimer's disease. In addition, rCBF in the MCI group was significantly increased in subjects who were carriers. Therefore, rCBF can be used as a biomarker to show disease progression in areas of the brain of MCI subjects.

Anxiety Affects Cognition Differently in Healthy Apolipoprotein E 4 Homozygotes and Non-Carriers

The authors investigated the effect of carrying the apolipoprotein epsilon4 allele on performance of cognitive tasks of executive functioning when anxiety was present. They studied 185 cognitively normal individuals matched for age, gender, education, cognitive test scores, psychotropic medications, and state- or trait-anxiety; some were homozygote carriers, some heterozygote, and some, non-carriers. A higher anxiety level was associated with poorer performance on the Trails B test in the e4 homozygote participants, which may be indicative of greater risk for subsequent cognitive decline.

Cellular effects of APOE4: Implications for Alzheimer's disease

The dominant risk factor for Alzheimer's disease (AD) is the epsilon-4 allele of apolipoprotein E (ApoE4). This allele confers increased risk for sporadic as well as familial AD disease. Individuals with two copies of the ApoE e4 allele have an approximately eight-fold increased risk of AD and have a significantly lower age of onset compared to AD patients not carrying this allele. Recent data indicate that the greater risk of AD associated with the ApoE4 isoform might relate to ApoE's susceptibility to proteolysis and neurotoxicity. However, the exact molecular mechanisms underlying ApoE and amyloid precursor protein (APP) interactions sub serving the risk-factor effect of ApoE4 remain unclear. The amyloid precursor protein, APP, has been shown to function as a molecular switch: cleavage at the beta, gamma, and caspase sites results in the production of four peptides-sAPPb (from which N-APP is derived), Ab, Jcasp, and C31-that mediate neurite retraction, synaptic reorganization, and ultimately programmedcell death. In contrast, cleavage at the alpha site produces the trophic peptide sAPPa and the inhibitor of APP gamma-site cleavage, aCTF. The decision between these two proteolytic pathways is governed at least in part by ligand binding: interaction with the axon guidance and trophic factor netrin-1 increases a-site cleavage, whereas interaction with the anti-trophin Ab inhibits alpha-site cleavage and increases net production of the four neurite-retractive peptides. Since this system exhibits positive feedback (e.g., Ab begets more Ab via APP processing, whereas aCTF inhibits Ab production), it is by definition prionic. Therefore, it is of interest to determine whether ApoE isoforms impact this trophic-anti-trophic peptide balance differentially, and, if so, by what mechanism. HEK-293T cells, B103-APP (rat neuroblastoma cells stably expressing human wild-type APP), 7W CHO cells (stably transfected with human APP751) and A172 human glioblastoma cells were used to determine whether ApoE, and in particular ApoE4, triggered alternative cellular APP processing that would provide a basis for understanding the cellular toxicity that has been reported previously. Transient transfection of cells was performed with Lipofectamine 2000. Whole-cell extracts were prepared and typically, 100mg of cell extract was loaded for SDS-PAGE and Western blot analysis. A total of 150-200 μg protein was also subjected to immunoprecipitation using specific antibodies to pull down the desired protein. The immunoprecipitated proteins were subjected to SDS-PAGE and Western blotting. The sAPPa, sAPPb, and Ab levels were obtained using the PerkinElmer (PE) AlphaLisa assay, and measurements were performed on an AlphaLisa reader. Immunocytochemistry was performed on cells 24 hrs after transfection with APP, ApoE, or the two in combination. The ApoE expression constructs were a kind gift from Dr. Yadong Huang of the Gladstone Institute. Cells were probed with primary antibodies and stained with an AlexaFluor secondary antibody (either 488 or 555). APP transcriptional activity was performed using the Gal4-APP system with a luciferase readout. Cells were harvested 48 h after transfection and the luciferase and b-galactosidase activities were determined with the Promega luciferase assay kit and the Promega b-galactosidase assay kit, respectively. ApoE3, ApoE4, and its proteolytic product ApoE4delta (ApoEdelta272) co-immunoprecipitated with full-length APP both in cell lysates and conditioned media. Interaction of APP with ApoE4 or ApoE4delta was accompanied by decreased sAPPa secretion and reduced sAPPa/Aß and sAPPa/sAPPß ratios as compared to ApoE3. Both ApoE4 and ApoE4δ reduced interaction between APP and Fe65 and also suppressed Fe65-mediated intracellular APPs.

APOE Genotype Results in Differential Effects on the Peripheral Clearance of Amyloid-β42 in APOE Knock-in and Knock-out Mice

The epsilon4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-beta (Abeta) is rapidly removed from the plasma by the liver and kidney and that the rate of its clearance is affected by ApoE in C57BL/6J and APOE-/- mice. To expand upon these findings, we assessed the peripheral clearance of human synthetic Abeta42 in APOE epsilon2, epsilon3, and epsilon4 knock-in and APOE knock-out mice injected with lipidated recombinant apoE2, E3, and E4 protein. Our results show that APOE does influence the rate at which the mice are able to clear Abeta42 from their bloodstream. Both APOE epsilon4 mice and APOE knock-out mice treated with lipidated recombinant apoE4 demonstrated increased retention of plasma Abeta42 over time compared to APOE epsilon2/APOE knock-out rE2 and APOE epsilon3/APOE knock-out rE3 mice. These findings suggest that the peripheral clearance of Abeta42 is significantly altered by APOE genotype. Given that APOE epsilon4 is a risk factor for AD, then these novel findings provide some insight into the role of ApoE isoforms on the peripheral clearance of Abeta which may impact on clearance from the brain.

Age‐Varying Association Between Statin Use and Incident Alzheimer's Disease

To determine whether risk reduction of statins for Alzheimer's disease (AD) varies by age or presence of apolipoprotein E (APOE) epsilon4 allele. A cohort of cognitively intact elderly participants was assessed biennially for dementia and AD. Community based. Three thousand three hundred ninety-two members of a health maintenance organization (HMO) aged 65 and older and without dementia. Statin use was identified from the HMO pharmacy database, and proportional hazards models were applied with statin use as a time-dependent covariate to assess the association between statins and AD and the modifying effects of age and the APOE epsilon4 allele. Over an average of 6.1 years of follow-up of 3,099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval (CI)=0.40-0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the association between statins and AD diminished with age (statin-by-age at entry interaction P=.04); the aHR in those younger than 80 was 0.44 (95% CI=0.25-0.78), versus 1.22 (95% CI=0.61-2.42) for aged 80 and older. The interaction term for statin use-by-APOE epsilon4 was not significant (P=.65). This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with a lower risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.

Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.

Apolipoprotein E-related all-cause mortality in hospitalized elderly patients

The most common apolipoprotein E (APOE) allelic variation is implicated in many age-related diseases and human longevity with controversial findings. We investigated the effect of APOE gene polymorphism on all-cause mortality in elderly patients taking into consideration the functional disability, cognitive impairment, malnutrition, and the occurrence of common age-related diseases. APOE genotypes were determined in 2,124 geriatric hospitalized patients (46.5% men and 53.5% women; mean age, 78.2 +/- 7.1 years; range, 65-100 years). At hospital admission, all patients underwent a comprehensive geriatric assessment to evaluate functional disability, cognitive status, nutritional status, and comorbidity. The main and secondary diagnoses at hospital discharge were also recorded. Mortality status was evaluated in all patients after a maximum follow-up of 5 years (range, from 1.26 to 5.23 years; median, 2.86 years). During the study period, 671 patients died (32.0%). At hospital admission, these patients showed a significant higher prevalence of cardiovascular diseases (56.3% vs 53.4%; p = 0.007), neoplasias (32.3% vs 13.7%; p < 0.001), and lower prevalence of neurodegenerative diseases (17.7% vs 20.7%; p < 0.001) than survived patients. Moreover, they also showed an higher prevalence of disability (52.0% vs 25.6%; p < 0.001), cognitive impairment (31.0% vs 18.8%; p < 0.001), and malnutrition (74.0% vs 46.1%; p < 0.001) than survived patients. In the overall study population, the APOE epsilon2 allele was significantly associated to neurodegenerative diseases (odds ratio = 0.59; 95% confidence interval (CI), 0.37-0.94). No significant association between the APOE polymorphism and disability, malnutrition, co-morbidity status, and with all-cause mortality was observed. In patients with cardiovascular diseases, however, a decreased risk of all-cause mortality was found in the epsilon2 allele carriers (hazard ratio = 0.56; 95% CI, 0.36-0.88). In this population, APOE allele variants might play a role on cardiovascular disease-related mortality.

Association Between NOS3 Gene G894T Polymorphism and Late-onset Alzheimer Disease in a Sample From Iran

Alzheimer disease (AD) is the most common age-associated neurodegenerative disease caused by complicated interactions between genetic and environmental factors. The presence of the apolipoprotein epsilon4 allele, the only confirmed genetic risk factor for late-onset AD (LOAD), is neither sufficient nor necessary to explain all occurrences of the disease. Aberrant expression of the endothelial nitric oxide synthase (NOS3) gene has been demonstrated in degenerating neurons and glial cells in brains with AD. Molecular epidemiologic studies have presented contradictory results concerning a potential role of NOS3 gene G894T polymorphism in AD. To define a possible association of this polymorphism with LOAD in an Iranian population, we conducted a case-control study including a clinically well-defined group of 100 LOAD patients and 100 age-matched controls. G894T polymorphism in NOS3 gene was determined by polymerase chain reaction-restriction fragment length polymorphisms assay. Chi-square analysis showed a significantly increased number of individuals with the G/G genotype in AD patients compared with controls (P<0.05). These results demonstrate an association between G894T polymorphism and LOAD in an Iranian sample and the G/G genotype seems to have some effects in the development of AD either alone or through interaction with other risk factors.

Apolipoprotein E Promoter Polymorphisms and Risk of Alzheimer's Disease: Evidence From Meta-Analysis

Apolipoprotein E (APOE) promoter polymorphisms have long been linked to Alzheimer disease (AD) susceptibility, although the established data remains controversial. Using meta-analysis, our study aimed to clarify the nature of the genetic risks contributed by the three polymorphisms for developing AD. Medline, Embase, and Alzgene search identified 40 studies with 9,662 cases and 9.696 controls. Both -491A/T polymorphism (AA vs AT + TT: OR = 1.49, 95% CI=1.29-1.72) and -219T/G polymorphism (TT vs TG + GG: OR=1.30, 95% CI=1.10-1.55) showed a significant association with AD susceptibility; however, significant association was not identified in the analysis for -427T/C polymorphism (TT vs TC + CC: OR =1.03, 95% CI= 0.82-1.30). Among the APOE epsilon 4} carriers, the -491A homozygotes were at higher risk to develop AD compared with the -491T carriers (OR=1.42, 95% CI =1.15-1.76). For subjects carrying the -491AA genotype, the presence of the APOE epsilon4 allele increased the risk of AD 4.37-fold (95% CI=3.43-5.56). Subgroup analysis restricted to the late-onset or the Caucasian individuals revealed a similar association as that identified without restriction regarding -491A/T polymorphism. Our results confirm a significant but modest association between APOE promoter -491A/T and -219T/G polymorphisms and AD susceptibility.