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 | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
<i>APOE</i> ε4 is associated with younger age at ischemic stroke onset but not with stroke outcome.
Lagging Cecilia C Lorentzen Erik E Stanne Tara M TM Pedersen Annie A Söderholm Martin M Cole John W JW Jood Katarina K Lemmens Robin R Phuah Chia-Ling CL Rost Natalia S NS Thijs Vincent V Woo Daniel D Maguire Jane M JM Lindgren Arne A Jern Christina C
Neurology 20191016 19
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Project description:IntroductionLarge genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke.MethodsAnalyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10-5 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts.ResultsIn the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found.DiscussionIn conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.
| S-EPMC11403718 | biostudies-literature
Project description:Large genome-wide association studies (GWAS) employing case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing age at onset (AAO) of ischemic stroke. Analyses were conducted in a Discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value < 1×10-5 in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant in APOE that encodes for the APOE-ϵ4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-ϵ4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.
| S-EPMC10705635 | biostudies-literature
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:Cortical thinning has been described in many neurodegenerative diseases and used for both diagnosis and disease monitoring. The imaging signatures of post-stroke vascular cognitive impairment have not been well described. We investigated the trajectory of cortical thickness over 3 years following ischaemic stroke compared to healthy stroke-free age- and sex-matched controls. We also compared cortical thickness between cognitively normal and impaired stroke survivors, and between APOE ɛ4 carriers and non-carriers. T1-weighted MRI and cognitive data for 90 stroke survivors and 36 controls from the Cognition And Neocortical Volume After Stroke (CANVAS) study were used. Cortical thickness was estimated using FreeSurfer volumetric reconstruction according to the Desikan-Killiany parcellation atlas. Segmentation inaccuracies were manually corrected and infarcted ipsilesional vertices in cortical thickness maps were identified and excluded using stroke lesion masks traced a-priori. Mixed-effects regression was used to compare cortical thickness cross-sectionally between groups and longitudinally between timepoints. Healthy control and stroke groups did not differ on demographics and most clinical characteristics, though controls were less likely to have atrial fibrillation. Age was negatively associated with global mean cortical thickness independent of sex or group, with women in both groups having significantly thicker cortex. Three months post-stroke, cortical thinning was limited and focal. From 3 months to 3 years, the rate of cortical thinning in stroke was faster compared to that in healthy controls. However, this difference in cortical thinning rate could not survive family-wise correction for multiple comparisons. Yet, cortical thinning at 3 years was found more spread especially in ipsilesional hemispheres in regions implicated in motor, sensory, and memory processing and recovery. The cognitively impaired stroke survivors showed greater cortical thinning, compared to controls, than those who were cognitively normal at 3 years. Also, carriers of the APOE ɛ4 allele in stroke exhibited greater cortical thinning independent of cognitive status. The temporal changes of cortical thickness in both healthy and stroke cohorts followed previously reported patterns of cortical thickness asymmetry loss across the human adult life. However, this loss of thickness asymmetry was amplified in stroke. The post-stroke trajectories of cortical thickness reported in this study may contribute to our understanding of imaging signatures of vascular cognitive impairment.
| S-EPMC9486118 | 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:BackgroundThere are contradicting reports on the associations between Apolipoprotein E4 (ApoE ε4) and brain outcomes in HIV with some evidence that relationships may be greatest in older age groups.MethodsWe assessed cognition in 76 clinically stable HIV-infected participants over age 60 and genotyped ApoE. Sixty-one of these subjects underwent structural brain magnetic resonance imaging and diffusion tensor imaging.ResultsThe median age of the participants was 64 years (range: 60-84) and the median estimated duration of HIV infection was 22 years. Apo ε4 carriers (n = 19) were similar to noncarriers (n = 57) in sex (95% vs. 96% male), and education (16.0 vs. 16.2 years) ApoE ε4 carriers demonstrated greater deficits in cognitive performance in the executive domain (P = 0.045) and had reduced fractional anisotropy and increased mean diffusivity throughout large white matter tracts within the brain compared with noncarriers. Tensor-based morphometry analyses revealed ventricular expansion and atrophy in the posterior corpus callosum, thalamus, and brainstem among HIV-infected ApoE ε4 carriers compared with ε4 noncarriers.ConclusionsIn this sample of older HIV-infected individuals, having at least 1 ApoE ε4 allele was associated with decreased cognitive performance in the executive functioning domain, reduced brain white matter integrity, and brain atrophy. Brain atrophy was most prominent in the posterior corpus callosum, thalamus, and brainstem. This pattern of cognitive deficit, atrophy, and damage to white matter integrity was similar to that described in HIV, suggesting an exacerbation of HIV-related pathology; although emergence of other age-associated neurodegenerative disorders cannot be excluded.
| S-EPMC5085854 | biostudies-literature
Project description:ObjectiveThe ε4 allele of apolipoprotein E (APOE) is the strongest known common genetic risk factor for Alzheimer's disease (AD) and alters age of onset in retrospective studies. Here, we longitudinally test the effects of APOE ε4 genotype and age during progression from normal cognition to AD.MethodsUsing data from 5381 cognitively normal older individuals and Cox proportional hazards models, we longitudinally tested the effects of APOE genotype on progression from normal cognition to mild cognitive impairment (MCI) or AD in four age strata (<60, 60-70, 70-80, 80 + ) and with a sliding window approach between ages 60 and 85.ResultsWe found that APOE ε4 carrier status and dosage significantly influenced progression to MCI or AD in all four age groups and that APOE ε4-associated progression risk peaked between ages 70 and 75. We confirmed APOE ε4-associated progression risk in a subset of the cohort with pathologically proven diagnoses.InterpretationOur findings indicate that in clinically normal individuals, APOE ε4 status significantly predicts progression to MCI or AD across older adulthood and that this risk varies with age. This information will be useful as therapeutic interventions become available and clinical decisions can be individually tailored based on age and genetic data.
| S-EPMC5018579 | biostudies-literature
Project description:BackgroundStroke incidence is decreasing in most developing countries. However, worrisome trends of an increase in the younger population have been described.AimTo investigate sex differences and longitudinal changes in ischemic stroke regarding incidence, cardiovascular risk factors, and outcome, in the young.MethodsThis is an observational study based on the data from the Swedish national stroke registry, Riksstroke. Patients, 18-54 years of age, having ischemic stroke between 2005 and 2018 were included, resulting in a study population of 16,210 patients.ResultsThe incidence was higher in men than in women (30.6 vs. 19.1 per 100,000, P < 0.001). After an initial increase, the incidence stabilized and then decreased, resulting in a similar level in 2018 as in 2005. Atrial fibrillation, diabetes, and usage of anti-hypertensives at stroke onset were more common among men and did not change over time. Smoking was common and slightly more so in women, but with a reduced prevalence in both men and women during the study period. Dependency in Activities of Daily Living (ADL) and case fatality showed no clear trends or sex differences.ConclusionsThe results show that there are sex differences in ischemic stroke in the younger age group regarding incidence and vascular risk factors, particularly smoking. Temporal trends in stroke incidence are difficult to interpret as fluctuations are substantial, largely due to stroke being quite uncommon in the younger population.
| S-EPMC8882967 | 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