APOE ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome.
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ABSTRACT:
SUBMITTER: Lagging C
PROVIDER: S-EPMC6946482 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and Purpose- APOE-ε4 genotype is a risk factor for sporadic Alzheimer disease and reduced recovery from brain injury. Since data on APOE genotype and dementia associated with transient ischemic attack/stroke are sparse, we determined the associations in a longitudinal population-based cohort. Methods- All patients with transient ischemic attack or stroke (2002-2012) in a defined population of 92 728 OxVASC (Oxford Vascular Study) had follow-up to 5-years. Pre-event and incident postevent dementia were ascertained through direct patient assessment and follow-up, supplemented by review of hospital/primary care records. Associations between pre- and post-event dementia and APOE genotype (ε4/ε4-homozygous and ε4/ε3-heterozygous versus ε3/ε3) were examined using logistic regression and Cox regression models, respectively, adjusted for age, sex, education, cerebrovascular burden (stroke severity, prior stroke, white matter disease), diabetes mellitus, and dysphasia. Results- Among 1767 genotyped patients (mean/SD age, 73.0/13.0 years, 901 [51%] male, 602 [34%] transient ischemic attack), 1058 (59.9%) were APOE-ε3/ε3, 403 (22.8%) were ε4/ε3 and 30 (1.7%) were ε4-homozygous. Homozygosity was associated with both pre-event (adjusted odds ratio, 5.81 [95% CI, 1.93-17.48]; P=0.002) and postevent dementia (adjusted hazard ratio, 3.64 [95% CI, 1.90-7.00]; P<0.0001). Association with postevent dementia was maintained after further adjustment for baseline cognitive impairment (hazard ratio, 2.41 [95% CI, 1.19-4.89]; P=0.01). There were no associations overall between ε4/ε3 and pre-event dementia (adjusted odds ratio, 1.47 [95% CI, 0.88-2.45]; P=0.14) or postevent dementia (hazard ratio, 1.11 [95% CI, 0.84-1.48]; P=0.47). Conclusions- In patients with transient ischemic attack and stroke, APOE-ε4 homozygosity was associated with both pre- and post-event dementia. Associations were independent of cerebrovascular burden and may be mediated through increased neurodegenerative pathology or vulnerability to injury.
| S-EPMC7224982 | biostudies-literature
Project description:The APOE ε4 allele is associated with cognitive deficits and brain atrophy in older adults, but studies in younger adults are mixed. We examined APOE genotype effects on cognition and brain structure in younger adults and whether genotype effects differed by age and with presence of depression. 157 adults (32 % ε4 carriers, 46 % depressed) between 20 and 50 years of age completed neuropsychological testing, 131 of which also completed 3 T cranial MRI. We did not observe a direct effect of APOE genotype on cognitive performance or structural MRI measures. A significant genotype by age interaction was observed for executive function, where age had less of an effect on executive function in ε4 carriers. Similar interactions were observed for the entorhinal cortex, rostral and caudal anterior cingulate cortex and parahippocampal gyrus, where the effect of age on regional volumes was reduced in ε4 carriers. There were no significant interactions between APOE genotype and depression diagnosis. The ε4 allele benefits younger adults by allowing them to maintain executive function performance and volumes of cingulate and temporal cortex regions with aging, at least through age fifty years.
| S-EPMC4972704 | biostudies-literature
Project description:PurposeTo explore temporal trends in age at first-ever ischemic stroke onset in a bi-ethnic, population-based study.MethodsCases of first-ever ischemic stroke (n = 3252) were identified in the Brain Attack Surveillance in Corpus Christi Project (2000-2012). Demographics and risk factors were abstracted from medical records. Trends in age at stroke onset were assessed overall and by ethnicity (Mexican American [MA] and non-Hispanic white [NHW]) using generalized additive models. Differences by ethnicity were tested by including an interaction term between time and ethnicity. Models were run unadjusted and adjusted for age of the population at risk for stroke.ResultsMean age at first-ever ischemic stroke significantly decreased from an average of 71.7 years in 2000 to an average of 69.3 years in 2012 (p = .0043). Ethnicity significantly modified the temporal trends (p < .001) with declines greater in NHWs than in MAs; mean age was estimated to decrease from 74.8 to 71.3 over the 13 years for NHWs, whereas for MAs, mean age was estimated to decrease from 68.9 to 66.9 after adjusting for ethnic-specific average age of the population at risk.ConclusionsAverage age at first-ever stroke onset declined over time in this community. Efforts should be made to prevent stroke by controlling risk factors before and during midlife.
| S-EPMC6162154 | biostudies-literature
Project description:To assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS). This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the APOE carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors. APOE ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for APOE ε4 heterozygosity or APOE ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for APOE carrier status. Along with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
| S-EPMC7217661 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to elucidate the factors that correlate with unfavorable outcomes and to develop a simple validated model for assessing risk of unfavorable outcomes in patients with minor ischemic stroke.MethodsThe derivation cohort included 1,313 patients hospitalized within 72 hours after onset with an initial NIH Stroke Scale score of 0 to 3 enrolled in a prospective, multicenter, observational study. Unfavorable outcome was defined as dependency (modified Rankin Scale score of 3-5) or death at 90 days. The predictive values of factors related to unfavorable outcome were evaluated. External validation was performed in 879 patients from a single-center stroke registry.ResultsIn the derivation cohort, a total of 203 patients (15%) had unfavorable outcomes. On multivariable analysis, women (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.30-2.94), age ?72 years (OR 2.80, 95% CI 1.83-4.36), intra/extracranial vascular occlusive lesion (OR 2.80, 95% CI 1.82-4.28), leg weakness (OR 1.72, 95% CI 1.06-2.82), and extinction/inattention (OR 5.55, 95% CI 1.30-21.71) were independently associated with unfavorable outcome. Patients having both a vascular lesion and either leg weakness or extinction/inattention showed 4.63 (95% CI 2.23-9.33) times the risk of unfavorable outcome compared with those having neither. In the validation cohort, the risk was similar, at 3.77 (95% CI 1.64-8.37).ConclusionsIntra- and extracranial vascular imaging, NIH Stroke Scale items such as leg weakness and extinction/inattention, and their combination, as well as female sex and advanced age, may be useful for predicting unfavorable outcomes in patients with minor stroke.
| S-EPMC4117175 | biostudies-literature
Project description:ObjectivePrior research suggests an acutely elevated risk of myocardial infarction and sudden cardiac death in the hour after coffee intake. However, the risk of ischemic stroke associated with transient exposure to coffee remains unclear. We hypothesized that caffeine intake is associated with a transiently increased risk of ischemic stroke.MethodsIn this multicenter case-crossover study, we interviewed 390 subjects (209 men, 181 women) between January 2001 and November 2006 a median of 3 days after acute ischemic stroke. Each subject's coffee consumption in the hour before stroke symptoms was compared with his or her usual frequency of consumption in the prior year.ResultsOf the 390 subjects, 304 (78%) drank coffee in the prior year, 232 within 24 hours and 35 within 1 hour of stroke onset. The relative risk (RR) of stroke in the hour after consuming coffee was 2.0 (95% confidence interval [CI], 1.4-2.8; p < 0.001). There was no apparent increase in risk in the hour following consumption of caffeinated tea (RR = 0.9, 95% CI 0.4-2.0; p = 0.85) or cola (RR = 1.0, 95% CI 0.4-2.4; p = 0.95). The association between ischemic stroke in the hour after coffee consumption was only apparent among those consuming ≤1 cup per day but not for patients who consumed coffee more regularly (p for trend = 0.002). Relative risks remained similar when the sample was restricted to those who were not simultaneously exposed to other potential triggers and the results remained significant after stratifying by time of day.ConclusionCoffee consumption transiently increases the risk of ischemic stroke onset, particularly among infrequent drinkers.
| S-EPMC3120108 | biostudies-literature
Project description:We previously observed the association of the co-occurrence of the HLA-DRB1 shared epitope (SE) and RANKL single-nucleotide polymorphisms (SNPs) with younger age at the onset of rheumatoid arthritis (RA) in 182 rheumatoid factor (RF)-positive European American patients with early-onset RA. The aim of this study was to fine-map the 48-kb RANKL region in the extended cohort of 210 European American RF-positive patients with early RA, to seek replication of RA-associated SNPs in additional RA cohorts of 501 European Americans and 298 African Americans, and to explore the functional consequences of RA-associated SNPs.SNP genotyping was conducted using pyrosequencing or TaqMan polymerase chain reaction (PCR) assays. Associations of rs7984870 with RANKL expression in plasma, peripheral blood mononuclear cells, and isolated T cells were quantified using enzyme-linked immunosorbent assay and reverse transcription-PCR. Site-directed mutagenesis of rs7984870 within the 2-kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay.A single promoter SNP, rs7984870, was consistently significantly associated with earlier age at the onset of RA in 3 independent seropositive (RF or anti-cyclic citrullinated peptide antibody) RA cohorts but not in seronegative RA patients. The C risk allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive patients with RA, significantly elevated RANKL messenger RNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to the transcription factor SOX5.The RANKL promoter allele that increased transcription levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to a younger age at the onset of RA in seropositive European American and African American patients.
| S-EPMC2944013 | biostudies-literature
Project description:Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5-77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6-70.3); however, noncarriers reached the threshold later at age 78 (76.1-84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.
| S-EPMC7609543 | biostudies-literature
Project description:BackgroundAn important cause of hemisensory syndrome is ischemic stroke. However, the diagnostic yield of neuroradiological imaging on hemisensory syndrome is low. Therefore, we aim to describe patients hospitalized with isolated hemisensory syndrome, and to identify clinical features associated with an aetiology of ischemic stroke.MethodsWe performed a single centre retrospective observation study, identifying patients who were hospitalised with hemisensory syndrome from October 2015 to March 2016, and whom underwent a magnetic resonance imaging (MRI) brain during the admission. Ischemic stroke was defined as the presence of restricted diffusion-weighted image on the MRI brain. Clinical information was analysed and compared between patients with and without stroke seen on MRI brain.Results79 patients, 36 (45.6%) males and 43 (54.4%) females, aged between 30 to 87 years (mean 54), were included in the final analysis. 18 (22.8%) patients were identified to have an acute ischemic stroke. Clinical features associated with ischemic stroke in hospitalised patients with hemisensory syndrome include symptom onset of ≤24 h at presentation (odds ratio 31.4, 95% CI 3.89-254.4), advanced age (odds ratio 1.14, CI 1.05-1.25) and smoking (odds ratio 7.35, 95% CI 1.20-45).ConclusionOlder patients, with a history of smoking, and who present with an acute onset of symptoms, are more likely to have ischemic stroke as the cause of their hemisensory syndrome.
| S-EPMC8077773 | biostudies-literature
Project description:The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have a distinct gene expression profile compare with rodent astrocytes. Human induced pluripotent stem cells (iPSCs) derived from individuals carrying specific gene variants or mutations provide an alternative cellular model more relevant to humans upon differentiation into specific cell types. Thus, we reprogramed human skin fibroblasts from cognitively normal individuals carrying APOE ε3/ε3 or ε4/ε4 genotype to iPSC clones and further differentiated them into neural progenitor cells and then astrocytes. We found that human iPSC-derived astrocytes secreted abundant apoE with apoE4 lipoprotein particles less lipidated compared to apoE3 particles. More importantly, human iPSC-derived astrocytes were capable of promoting neuronal survival and synaptogenesis when co-cultured with iPSC-derived neurons with APOE ε4/ε4 astrocytes less effective in supporting these neurotrophic functions than those with APOE ε3/ε3 genotype. Taken together, our findings demonstrate APOE genotype-dependent effects using human iPSC-derived astrocytes and provide novel evidence that the human iPSC-based model system is a strong tool to explore how apoE isoforms contribute to neurodegenerative diseases.
| S-EPMC5886091 | biostudies-literature