APOE e4 Genotypes Increase Risk of Delirium During COVID-19-Related Hospitalizations: Evidence From a Large UK Cohort.
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ABSTRACT:
SUBMITTER: Kuo CL
PROVIDER: S-EPMC8344705 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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APOE e4 Genotypes Increase Risk of Delirium During COVID-19-Related Hospitalizations: Evidence From a Large UK Cohort.
Kuo Chia-Ling CL Pilling Luke C LC Atkins Janice L JL Fortinsky Richard H RH Kuchel George A GA Melzer David D
The journals of gerontology. Series A, Biological sciences and medical sciences 20220401 4
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| S-EPMC7314139 | biostudies-literature
Project description:BackgroundThe independent and additive associations of walking pace and grip strength on dementia risk and the potential modifying effects of age, APOE phenotypes, and other dementia risk factors on the walking pace and dementia relationships demand further clarification. We aimed to investigate the independent and additive relationships of walking pace and handgrip strength on the risk of new-onset dementia and examine the potentially modifying effects of age, APOE phenotypes, lifestyle factors, and family history of dementia in the relationships.MethodsA total of 495,700 participants from the UK Biobank, who were free of dementia at baseline, were included in this study. Walking pace was self-defined as slow, average, or brisk. Handgrip strength was assessed by dynamometer and was divided into sex-specific quartiles. The APOE genotypes were determined by a combination variant of rs429358 and rs7412. Other dementia risk factors, including education, physical activity, hypertension, depression, diabetes, and family history of dementia, were also collected. The primary outcome was new-onset all-cause dementia.ResultsOver a median follow-up duration of 12.0 years, 3986 (0.8%) participants developed new-onset all-cause dementia. Compared with those with slow walking pace, participants with average (HR, 0.61; 95%CI: 0.55-0.68) or brisk (HR, 0.59; 95%CI: 0.52-0.67) walking pace had a significantly lower risk of new-onset all-cause dementia. Moreover, compared with those with both slow walking pace and lower handgrip strength (the first quartile), the lowest risk of new-onset all-cause dementia was observed in participants with both average or brisk walking pace and higher handgrip strength (the 2-4 quartiles) (HR, 0.45; 95%CI: 0.40-0.52). Notably, the negative relationship between walking pace and the risk of new-onset all-cause dementia was significantly reduced as APOE ε4 dosage increased (APOE ε4 dosages = 0 or 1: brisk vs. slow: HR, 0.55; 95%CI: 0.48-0.63; vs. APOE ε4 dosages = 2: brisk vs. slow: HR, 1.14; 95%CI: 0.77-1.68; P for interaction = 0.001) or age increased (< 58 [median]: brisk vs. slow: HR, 0.27; 95%CI: 0.18-0.41; vs. ≥ 58 years: brisk vs. slow: HR, 0.55; 95%CI: 0.48-0.63; P for interaction = 0.007).ConclusionsWalking pace was inversely associated with new-onset dementia in the general population, especially in younger participants and those with lower APOE ε4 dosage. Participants with both faster walking pace and higher handgrip strength had the lowest risk of dementia, suggesting that maintaining both high handgrip strength and fast walking pace may be a more comprehensive strategy for preventing dementia risk.
| S-EPMC9827642 | biostudies-literature
Project description:There is evidence to suggest that the APOE ?4 allele (which confers an increased risk of developing dementia) might be associated with cognitive advantages earlier in life. Further, nicotine might selectively benefit ?4 carriers. We used fMRI to explore performance on a prospective memory (PM) task in young adults (age 18-30) with and without nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in ?4 carriers, but not in ?3 carriers. In an event-related analysis, extrastriate responses to PM trials were enhanced by nicotine only in ?4 carriers. These differences in early visual processing may contribute to the behavioral findings. Activity in medial BA10 (previously implicated in PM) differentiated ?4 from ?3 carriers. One BA10 subregion showed greater deactivation in ?4 carriers during PM trials. Activity in other BA10 subregions was modulated by PM reaction time, pointing to region-specific effects within medial BA10. In addition, activity in right hippocampal formation was only seen in ?4 carriers receiving nicotine. These results demonstrate that cognitive enhancement by nicotine can selectively benefit APOE ?4 carriers, and point to genotype-specific differences in neural activity during PM. In addition, these results show that the role of medial BA10 in PM likely involves varying contributions from functionally specific subregions.
| S-EPMC3572462 | biostudies-literature
Project description:PurposeApoE-e4 has a well-established connection to late-onset Alzheimer disease (AD) and is available clinically. Yet, there have been no analyses of payer coverage policies for ApoE. Our objective was to analyze private payer coverage policies for ApoE genetic testing, examine the rationales, and describe supporting evidence referenced by policies.MethodsWe searched for policies from the eight largest private payers (by member numbers) covering ApoE testing for late-onset AD. We implemented content analysis methods to evaluate policies for coverage decisions and rationales.ResultsSeven payers had policies with positions on ApoE testing. Five explicitly state they do not cover ApoE and two apply generic preauthorization criteria. Rationales supporting coverage decisions include: reference to guidelines or national standards, inadequate data supporting testing, characterizing testing as investigational, or that testing would not alter patients' clinical management.ConclusionSeven of the eight largest private payers' coverage policies reflect standards that discourage ApoE testing due to a lack of clinical utility. As the field advances, ApoE testing may have an important clinical role, particularly considering that disease-modifying therapies are under evaluation by the US Food and Drug Administration. These types of field advancements may not be consistent with private payers' policies and may cause payers to reevaluate existing coverage policies.
| S-EPMC8035237 | biostudies-literature
Project description:ObjectiveSubjective cognitive decline and APOE e4 allele (APOE4) are known predictors of mild cognitive impairment and dementia (mild cognitive impairment/dementia), with recent evidence showing interaction between subjective cognitive decline and APOE4 in amplifying the risk of mild cognitive impairment/dementia. However, the literature is unclear whether the interaction effect is seen across various age and sex strata. This study examined the interaction between subjective cognitive decline and APOE4-across different age and sex strata-on the risk of mild cognitive impairment/dementia.MethodsThis cohort study included 16,221 participants aged ⩾50 years and had normal cognition at baseline. Participants were evaluated for subjective cognitive decline and APOE4 at baseline, and followed-up almost annually for mild cognitive impairment/dementia (median follow-up = 4.5 years). Interaction effects were examined in Cox regression using Relative Excess Risk due to Interaction, stratified by age (⩽70 vs >70 years) and sex.ResultsSubjective cognitive decline and APOE4 were independently associated with mild cognitive impairment/dementia (hazard ratio: 1.4-1.8), with the highest risk when subjective cognitive decline and APOE4 co-occurred (hazard ratio: 2.6). APOE4 amplified the association between subjective cognitive decline and mild cognitive impairment/dementia in older women (Relative Excess Risk due to Interaction 1.0; 95% confidence interval = [0.3, 1.6]), but not in other age or sex strata. Among older women, half of them developed mild cognitive impairment/dementia by 12.1 years in the absence of subjective cognitive decline or APOE4. This duration shortened to 8.1-10.3 years in the presence of either subjective cognitive decline or APOE4, and to 4.4 years in the presence of both subjective cognitive decline and APOE4. Interaction effect among older women remained consistent when alternate outcomes were used (i.e. mild cognitive impairment and dementia due to Alzheimer's disease; dementia; and Alzheimer's dementia) (Relative Excess Risk due to Interaction 1.2-2.5).ConclusionsAPOE4 amplifies the association between subjective cognitive decline and neurocognitive disorders in older women, with the findings suggesting the need for further research to delineate underlying neurobiology. APOE4 may potentially have a role in facilitating further risk stratification of older women with subjective cognitive decline in clinical practice.
| S-EPMC9433458 | biostudies-literature
Project description:Genome-wide mRNA expression profiles of 31 primary gastric tumors from the UK patient cohort. Gastric cancer (GC) is the second leading cause of global cancer mortality, with individual gastric tumors displaying significant heterogeneity in their deregulation of various oncogenic pathways. We aim to identify major oncogenic pathways in GC that robustly impact patient survival and treatment response. We used an in silico strategy based on gene expression signatures and connectivity analytics to map patterns of oncogenic pathway activation in 25 unique GC cell lines, and in 301 primary gastric cancers from three independent patient cohorts. Of 11 oncogenic pathways previously implicated in GC, we identified three predominant pathways (proliferation/stem cell, NF-kB, and Wnt/b-catenin) deregulated in the majority (>70%) of gastric tumors. Using a variety of proliferative, Wnt, and NF-kB-related assays, we experimentally validated the pathway predictions in multiple GC cell lines showing similar pathway activation patterns in vitro. Patients stratified at the level of individual pathways did not exhibit consistent differences in clinical outcome. However, patients grouped by oncogenic pathway combinations demonstrated robust and significant survival differences (e.g., high proliferation/high NF-kB vs. low proliferation/low NF-kB), suggesting that tumor behavior in GC is likely influenced by the combined effects of multiple oncogenic pathways. Our results demonstrate that GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Keywords: gastric cancer, cell culture
2009-10-06 | GSE15456 | GEO
Project description:Alzheimer's disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., "angiogenesis") in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as TREM2 and positively correlated with pathology severity in APOE4 carriers, but negatively in non-carriers. Overall, cumulative evidence from the largest neuroimaging, pathology, and transcriptomic studies available suggests that vascular dysfunction is key to the development of AD in APOE4 carriers. However, further studies are required to tease out non-APOE4-specific mechanisms.
| S-EPMC9266739 | biostudies-literature
Project description:BackgroundPulmonary function is increasingly recognized as a key factor in metabolic diseases. However, its link to gout risk remains unclear. The study aimed to investigate the relationship between pulmonary function and the risk of developing gout and the underlying biological mechanisms.MethodsOur study included 420,002 participants with complete pulmonary function data from the UK Biobank. Logistic regression was used to evaluate gout prevalence among individuals with different pulmonary function statuses. Propensity score matching (PSM) created balanced groups, while Cox regression gauged the risk association between reduced lung capacity and gout compared with normal function. Mendelian randomization (MR) analysis was used to verify causal associations. Non-linear correlations were assessed with restricted cubic spline (RCS) analysis, and mediation analysis was used to explore the role of blood biomarkers. Mediation analyses were used to investigate the potential mediating role of biomarkers in the association.ResultsCross-sectional analysis revealed a higher prevalence of gout in individuals with preserved ratio of impaired spirometry (PRISm) of 6.31% and chronic obstructive pulmonary disease (COPD) of 6.26% than in those with normal pulmonary function (3.45%). After adjustment for covariates, both PRISm (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.17-1.31) and COPD (OR 1.14, 95% CI 1.07-1.22) were significantly associated with gout. Longitudinal analysis confirmed that impaired pulmonary function significantly increased the risk of developing gout (hazard ratio [HR] 1.32, 95% CI 1.24-1.40). MR further revealed a potential causal effect of decreased pulmonary function on an increased risk of gout. Subgroup analysis revealed significant interactions between impaired pulmonary function and several factors, including body mass index (BMI), levels of physical activity, and diabetes status, in their associations with the risk of gout. RCS analysis showed a nonlinear relationship between pulmonary function indicators and gout incidence, characterized by an inverse S-shaped curve. Mediation analysis revealed that urate levels (49.1% mediation proportion), C-reactive protein (CRP) levels (6.62%), monocyte counts (1.33%), and neutrophil counts (4.85%) significantly mediated the relationship between pulmonary function and the risk of gout.ConclusionsOur study revealed a significant association between impaired pulmonary function and an increased risk of developing gout. The association might be partially mediated by biomarkers including urate levels, inflammatory markers, and immune cell counts.
| S-EPMC11686989 | biostudies-literature
Project description:The apolipoprotein E (APOE) e4 allele is strongly associated with increased risk of cognitive impairments in older adulthood. There is also a possible link to enhanced cognitive performance in younger adults, and the APOE e4 allele may constitute an example of antagonistic pleiotropy. The aim of this work was to investigate the cognitive and neural (functional) effects of the APOE e4 allele during mid-age (45-55 years), where a transition toward cognitive deficit might be expected. APOE e4 carriers (e4+) were compared with non-e4 carriers (e4-) on tasks of sustained and covert attention and prospective memory, and functional magnetic resonance imaging data acquired. Performance by e4+ was equivalent or better than e4- on all 3 tasks, although performance benefits were less pronounced than in youth. Neurally, e4+ showed less task-related recruitment of extrastriate and parietal areas. This became more evident when neural activation data were compared with that of young adults acquired in a parallel study. As expected, mid-age participants showed more diffuse neural activation. Notable was the fact that e4+ showed a relative inability to recruit parietal regions as they aged. This was coupled with a tendency to show greater recruitment of frontal regions, and underactivation of extrastriate visual regions. Thus, mid-age e4+ show a pattern of neural recruitment usually seen later in life, possibly reflecting the source of an accelerated aging profile that describes the e4 genotype.
| S-EPMC4001126 | biostudies-literature
Project description:The aim of this study was to investigate whether cognitive performance was equally influenced by Apolipoprotein E (APOE, with its three alleles, e2, e3, and e4) in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). In addition, we examined a group of patients with a combination of Vascular dementia (VaD) and AD (VaD/AD). We asked if the APOE e4 allele influenced cognition in these patient groups in the same way. Our study comprised data from 1,991 patients (55% women), with a mean age of 70.9 years (SD 10.8) and 12.1 years of education (SD 3.8). Of them, 1,111 (56%) had at least one APOE e4 allele; 871 (44%) had one and 240 (12%) had two e4 alleles. Three neurocognitive tests were used to measure cognition: the Mini Mental State Examination (MMSE), the 10-word test of the Consortium to Establish a Registry for Alzheimer's Disease Word List (CERAD-WL) (immediate and delayed recall), and the Trail Making Test Part A (TMTA). The APOE genotypes were regressed against cognitive function using linear regression, adjusting for diagnosis, age, sex, and education. The interaction diagnosis∗APOE was investigated. The allele type had the largest effect on cognitive performance assessed by the CERAD-WL delayed recall test, less for the other tests. Those without the e4 type scored 0.7 units better than those with e4 allele(s) (p < 0.001). Furthermore, there was a significant inverse dose-response pattern between number of e4 alleles and cognitive performance; those with one allele scored 0.4 units better than those with two alleles (p = 0.006), and those without e4 scored 0.7 units better than those with one e4 (p < 0.001). This pattern did not differ between the four diagnostic groups studied.
| S-EPMC8236580 | biostudies-literature