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• The time-by-APOE ε4 interaction on brain FC demonstrates at a young age. • After follow-up for nearly 3 years, young ε4 carriers reveal decreased FC among time. • And the left superior temporal gyrus is the most sensitive brain region. APOE ε4 is risk for cognitive decline even in normal aging, but its effect on the whole-brain functional connectivity (FC) among time in young adults remain elusive. This study aimed to validate the time-by- APOE ε4 interaction on brain FC of this specific population. Longitudinal changes in neuropsychological assessments and resting-state functional magnetic resonance imaging in 26 ε4 carriers and 26 matched non- ε4 carriers were measured for about 3 years. Whole-brain FC was calculated, and a full factorial design was used to compare the difference among groups. Two-sample t test was used for post-hoc analysis. Pearson's correlation analysis was conducted to investigate the relationships between FC and cognitive tests. Of 26 specially appointed ROIs, left superior temporal gyrus (TG) was most sensitive to the effect of time-by-gene interaction. Specifically, the alteration of FC was distributed between the left TG and right TG with GRF correction (voxel- P < 0.001, cluster- P < 0.05), and decreased in ε4 carriers while increased in non- ε4. The main effect of gene showed ε4 carriers has lower FC between left TG and right middle frontal gyrus as compared with non- ε4 both at baseline and follow-up study; ε4 carriers has lower FC between left TG and right supramarginal as compared with non- ε4 at baseline, but no difference in follow-up study. The time-by- APOE ε4 interaction on brain FC was demonstrated at a young age, and left TG was the earliest affected brain regions. The young adult ε4 carriers experience decreased FC among time in the absence overt clinical symptoms. [ABSTRACT FROM AUTHOR]

Disrupted alternative splicing plays a determinative role in neurological diseases, either as a direct cause or as a driver in disease susceptibility. Transcriptomic profiling of aged human postmortem brain samples has uncovered hundreds of aberrant mRNA splicing events in Alzheimer's disease (AD) brains, associating dysregulated RNA splicing with disease. We previously identified a complex array of alternative splicing combinations across apolipoprotein E receptor 2 (APOER2), a transmembrane receptor that interacts with both the neuroprotective ligand Reelin and the AD-associated risk factor, APOE. Many of the human APOER2 isoforms, predominantly featuring cassette splicing events within functionally important domains, are critical for the receptor's function and ligand interaction. However, a comprehensive repertoire and the functional implications of APOER2 isoforms under both physiological and AD conditions are not fully understood. Here, we present an in-depth analysis of the splicing landscape of human APOER2 isoforms in normal and AD states. Using single-molecule, long-read sequencing, we profiled the entire APOER2 transcript from the parietal cortex and hippocampus of Braak stage IV AD brain tissues along with age-matched controls and investigated several functional properties of APOER2 isoforms. Our findings reveal diverse patterns of cassette exon skipping for APOER2 isoforms, with some showing region-specific expression and others unique to AD-affected brains. Notably, exon 15 of APOER2, which encodes the glycosylation domain, showed less inclusion in AD compared to control in the parietal cortex of females with APOE ɛ3/ɛ3 genotype. Also, some of these APOER2 isoforms demonstrated changes in cell surface expression, APOE-mediated receptor processing, and synaptic number. These variations are likely critical in inducing synaptic alterations and may contribute to the neuronal dysfunction underlying AD pathogenesis. Author summary: Alternative splicing enhances genetic diversity by producing various RNA isoforms from a single gene. The gene LRP8, which encodes apolipoprotein E receptor 2 (APOER2), undergoes extensive alternative splicing in the brain. APOER2 is a type I transmembrane receptor that interacts with extracellular ligands, notably the neuroprotective Reelin and APOE, a risk factor associated with Alzheimer's disease (AD). Interestingly, alternative splicing of APOER2 has been shown to be altered in AD; yet the complete repertoire of APOER2 isoforms in both normal and AD-affected brains remained largely unexplored. Our study offers insight into the diverse isoforms of APOER2 in the human brain and their splicing modifications in the context of AD. We discovered a range of combinatorial APOER2 alternative splicing events, leading to a diverse set of isoforms in the human brain. Our analysis revealed both region- and disease-specific APOER2 isoforms, indicating that APOER2 splicing is not only spatially regulated but also undergoes alterations in AD. Moreover, we observed that some of the APOER2 isoforms in AD brains show changes in cell surface expression, receptor processing and synapse numbers. These findings suggest that combinatorial splicing of APOER2 is a critical determinant of its protein function and undergoes significant alterations in AD. [ABSTRACT FROM AUTHOR]

The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer's disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP , contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in- cis genes at the MAPT and RPSA - MOBP loci. The association with the MAPT (H1c clade) and RPSA - MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA - MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA - MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex. We identified associations at the MAPT , APOE , and MOBP loci with FTD, suggesting potential common genetic denominators across multiple neurological conditions (i.e., FTD, PSP, ALS, AD, PD, and CBD). These findings will aid in the further characterization of the common and disease-specific pathogenesis of, and interventions for, these disorders. [ABSTRACT FROM AUTHOR]

Phenome-wide association studies (PheWAS) facilitate the discovery of associations between a single genetic variant with multiple phenotypes. For variants which impact a specific protein, this can help identify additional therapeutic indications or on-target side effects of intervening on that protein. However, PheWAS is restricted by an inability to distinguish confounding due to linkage disequilibrium (LD) from true pleiotropy. Here we describe CoPheScan (Coloc adapted Phenome-wide Scan), a Bayesian approach that enables an intuitive and systematic exploration of causal associations while simultaneously addressing LD confounding. We demonstrate its performance through simulation, showing considerably better control of false positive rates than a conventional approach not accounting for LD. We used CoPheScan to perform PheWAS of protein-truncating variants and fine-mapped variants from disease and pQTL studies, in 2275 disease phenotypes from the UK Biobank. Our results identify the complexity of known pleiotropic genes such as APOE, and suggest a new causal role for TGM3 in skin cancer. Understanding pleiotropic genetic associations across multiple phenotypes, which could lead to understanding of common disease mechanisms or therapeutics. Here, the authors present CoPheScan, a Bayesian method for PheWAS which detects genetic associations with multiple phenotypes and distinguishes pleiotropy from LD-confounding. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnoea (OSA) is commonly associated with insulin resistance (IR) and dyslipidaemia. Apolipoprotein E (APOE) plays important roles in lipid metabolism. The study aimed to disentangle the multifactorial relationships between IR and APOE based on a large-scale population with OSA. Methods: A total of 5,591 participants who underwent polysomnography for OSA diagnosis were finally enrolled. We collected anthropometric, fasting biochemical and polysomnographic data for each participant. Linear regression analysis was performed to evaluate the relationships between APOE, IR, and sleep breathing-related parameters. Logistic regression, restricted cubic spline (RCS) and mediation analyses were used to explore relationships between APOE and IR in patients with OSA. Results: Increasing OSA severity was associated with greater obesity, more obvious dyslipidaemia, and higher levels of APOE and IR. APOE was positively correlated with the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and microarousal index (MAI) even after adjusting for age, sex, body mass index, and smoking and drinking levels (β = 0.107, β = 0.102, β = 0.075, respectively, all P < 0.001). The risks of IR increased from the first to fourth quartiles of APOE (odds ratio (OR) = 1.695, 95% CI: 1.425–2.017; OR = 2.371, 95% confidence interval (CI): 2.009–2.816; OR = 3.392, 95% CI: 2.853–4.032, all P < 0.001) after adjustments. RCS analysis indicated non-linear and dose response relationships between APOE, AHI, ODI, MAI and insulin resistance. Mediation analyses showed that HOMA-IR explained 9.1% and 10% of the association between AHI, ODI and APOE. The same trends were observed in men, but not in women. Conclusions: This study showed that APOE is a risk factor for IR; moreover, IR acts as a mediator between OSA and APOE in men. APOE, IR, and OSA showed non-linear and multistage relationships. Taken together, these observations revealed the complex relationships of metabolic disorders in patients with OSA, which could lead to the development of new treatment modalities and a deeper understanding of the systemic impact of OSA. [ABSTRACT FROM AUTHOR]

Background: Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD. This is despite reduced abundance and function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD, which can impact brain exposure of drugs. The fundamental mechanisms leading to reduced P-gp abundance in sporadic AD remain unknown; however, it is known that the apolipoprotein E (apoE) gene has the strongest genetic link to sporadic AD development, and apoE isoforms can differentially alter BBB function. The aim of this study was to assess if apoE affects P-gp abundance and function in an isoform-dependent manner using a human cerebral microvascular endothelial cell (hCMEC/D3) model. Methods: This study assessed the impact of apoE isoforms on P-gp abundance (by western blot) and function (by rhodamine 123 (R123) uptake) in hCMEC/D3 cells. Cells were exposed to recombinant apoE3 and apoE4 at 2 – 10 µg/mL over 24 – 72 hours. hCMEC/D3 cells were also exposed for 72 hours to astrocyte-conditioned media (ACM) from astrocytes expressing humanised apoE isoforms. Results: P-gp abundance in hCMEC/D3 cells was not altered by recombinant apoE4 relative to recombinant apoE3, nor did ACM containing human apoE isoforms alter P-gp abundance. R123 accumulation in hCMEC/D3 cells was also unchanged with recombinant apoE isoform treatments, suggesting no change to P-gp function, despite both abundance and function being altered by positive controls SR12813 (5 µM) and PSC 833 (5 µM), respectively. Conclusions: Different apoE isoforms have no direct influence on P-gp abundance or function within this model, and further in vivo studies would be required to address whether P-gp abundance or function are reduced in sporadic AD in an apoE isoform-specific manner. [ABSTRACT FROM AUTHOR]

The apolipoprotein E (APOE) ε4 is a well‐established risk factor of amyloid‐β (Aβ) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non‐demented and have Aβ pathology. There are limited studies on assessing Aβ status and clinical conversion in the APOE ε3/ε3 non‐demented population. Two hundred and ninety‐three non‐demented individuals with APOE ε3/ε3 from ADNI database were divided into Aβ‐positron emission tomography (Aβ‐PET) positivity (+) and Aβ‐PET negativity (−) groups using cut‐off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aβ‐PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aβ‐PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p‐tau 181 and WMH can accurately predict Aβ‐PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non‐invasive and effective tool to improve the efficiency of screening Aβ‐PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials. [ABSTRACT FROM AUTHOR]

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (H1R) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using Apolipoprotein E-knockout (ApoE−/−) mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC−/−) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. Key messages: Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE−/− mice. Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. [ABSTRACT FROM AUTHOR]

Whole-brain radiation therapy (WBRT) is a common treatment for brain metastases and is frequently associated with decline in neurocognitive functioning (NCF). The e4 allele of the apolipoprotein E (APOE) gene is associated with increased risk of Alzheimer disease and NCF decline associated with a variety of neurologic diseases and insults. APOE carrier status has not been evaluated as a risk factor for onset time or extent of NCF impairment in patients with brain metastases treated with WBRT. NRG/Radiation Therapy Oncology Group 0614 treated adult patients with brain metastases with 37.5 Gy of WBRT (+/– memantine), performed longitudinal NCF testing, and included an optional blood draw for APOE analysis. NCF test results were compared at baseline and over time with mixed-effects models. A cause-specific Cox model for time to NCF failure was performed to assess the effects of treatment arm and APOE carrier status. APOE results were available for 45% of patients (n = 227/508). NCF did not differ by APOE e4 carrier status at baseline. Mixed-effects modeling showed that APOE e4 carriers had worse memory after WBRT compared with APOE e4 noncarriers (Hopkins Verbal Learning Test–Revised total recall [least square mean difference, 0.63; P =.0074], delayed recognition [least square mean difference, 0.75; P =.023]). However, APOE e4 carrier status was not associated with time to NCF failure (hazard ratio, 0.86; 95% CI, 0.60-1.23; P =.40). Memantine delayed the time to NCF failure, regardless of carrier status (hazard ratio, 0.72; 95% CI, 0.52-1.01; P =.054). APOE e4 carriers with brain metastases exhibited greater decline in learning and memory, executive function, and the Clinical Trial Battery Composite score after treatment with WBRT (+/– memantine), without acceleration of onset of difference in time to NCF failure. [ABSTRACT FROM AUTHOR]

Recent research suggests that the retrieval of autobiographical memories among cognitively healthy middle‐aged and older adults is sensitive to the Apolipoprotein E ε4 (APOE4) allele, a genetic marker that increases the risk of Alzheimer's disease (AD) dementia. However, whether the APOE4‐associated alteration in autobiographical memory retrieval encompasses rapid (i.e. direct retrieval) or iterative (i.e. generative retrieval) processes remains unclear. In the present study, 39 APOE4 carriers and 45 non‐carriers (ages 60–80) who scored within normal limits on neuropsychological testing were cued to generate specific autobiographical events. We examined group differences in direct and generative retrieval and correlated direct and generative retrieval rates with performance on neuropsychological tests. Direct retrieval rates were lower in the APOE4 carriers compared to non‐carriers. Episodic memory positively correlated with direct retrieval rates across the sample, though this relationship became non‐significant when factoring in age and sex. There were no significant findings related to successful generative retrieval rates and its efficiency. In summary, compared to non‐carriers, cognitively unimpaired middle‐aged to older adult APOE4 carriers demonstrated greater difficulty, rapidly reconstructing specific autobiographical events without the support of semantic memory, suggesting that early autobiographical memory retrieval processes demonstrate vulnerability to AD‐related risk factors. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether prognosis of patients with hepatocellular carcinoma (HCC) is affected by the abundance and subgroups of myeloid-derived suppressor cells (MDSCs) as well as subtypes and expression of apolipoprotein E (apoE). Methods: 31 HCC patients were divided into three groups according to blood total apoE level for detecting the abundance of immunoregulatory cells by flow cytometry. Tumour tissue microarrays from 360 HCC patients were evaluated about the abundance and subgroups of MDSCs and the expression of apoE2, apoE3, apoE4 by immunofluorescence staining and immunohistochemistry staining. Survival analysis by means of univariate, multivariate COX regression and Kaplan-Meier methods of the 360 patients was performed based on clinical and pathological examinations along with 10 years’ follow-up data. Results: The lower apoE group presented higher abundance of MDSCs in the peripheral blood of HCC patients than higher apoE group. The abundance of monocyte-like MDSCs (M-MDSCs) was higher in the apoE low level group than high level group (p = 0.0399). Lower H-score of apoE2 (HR = 6.140, p = 0.00005) and higher H-score of apoE4 (HR = 7.001, p = 0.009) in tumour tissue were significantly associated with shorter overall survival (OS). The higher infiltration of polymorphonuclear granulocyte-like MDSCs (PMN-MDSCs, HR = 3.762, p = 0.000009) and smaller proportion of M-MDSCs of total cells (HR = 0.454, p = 0.006) in tumour tissue were independent risk factors for shorter recurrence-free survival (RFS). Conclusion: The abundance of MDSCs in HCC patients’ plasma negatively correlates with the level of apoE. The expression of apoE4 in HCC tissue indicated a poor prognosis while apoE2 might be a potential protective factor. [ABSTRACT FROM AUTHOR]

Introduction: Recent evidence suggests that the influence of verbal intelligence and education on the onset of subjective cognitive decline may be modulated by gender, where education contributes less to cognitive resilience (CR) in women than in men. This study aimed to examine gender differences in the association between CR and mild cognitive impairment (MCI) incidence in an Australian population-based cohort. Methods: We included 1,806 participants who had completed at least the first two waves and up to four waves of assessments in the Personality and Total Health (PATH) Through Life study (baseline: 49% female, male = 62.5, SD = 1.5, age range = 60–66 years). CR proxies included measures of educational attainment, occupation skill, verbal intelligence, and leisure activity. Discrete-time survival analyses were conducted to examine gender differences in the association between CR proxies and MCI risk, adjusting for age and apolipoprotein E4 status. Results: Gender differences were only found in the association between occupation and MCI risk, where lower occupation skill was more strongly associated with higher risk in men than in women (odds ratio [OR] = 1.30, 95% confidence interval [CI] [1.07, 1.57]). In both genders, after adjusting for education and occupation, one SD increase in leisure activity was associated with lower MCI risk by 32% (OR = 0.76, 95% CI [0.65, 0.89]). Higher scores in verbal intelligence assessment were associated with reduced risk of MCI by 28% (OR = 0.78, 95% CI [0.69, 0.89]). Conclusion: Occupational experience may contribute to CR differently between genders. Life course cognitive engagement and verbal intelligence may be more protective against MCI than education and occupation for both men and women. [ABSTRACT FROM AUTHOR]

The apolipoprotein E (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often copresent with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenges. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. In addition, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing. NEW & NOTEWORTHY: This study is the first to use whole body plethysmography (WBP) to measure the impact of APOE alleles on breathing under normoxia and during adverse respiratory challenges in a targeted replacement Alzheimer's model. Both sex and genotype were shown to affect breathing under normoxia, hypoxic challenge, and hypoxic-hypercapnic challenge. This work has important implications regarding the impact of genetics on respiratory control as well as applications pertaining to conditions of disordered breathing including sleep apnea and neurotrauma. [ABSTRACT FROM AUTHOR]

Amyloid beta (Aβ) follows a sigmoidal time function with varying accumulation rates. We studied how the position on this function, reflected by different Aβ accumulation phases, influences APOE ɛ4's association with Aβ and cognitive decline in 503 participants without dementia using Aβ-PET imaging over 5.3-years. First, Aβ load and accumulation were analyzed irrespective of phases using linear mixed regression. Generally, ɛ4 carriers displayed a higher Aβ load. Moreover, Aβ normal (Aβ-) ɛ4 carriers demonstrated higher accumulation. Next, we categorized accumulation phases as "decrease", "stable", or "increase" based on trajectory shapes. After excluding the Aβ-/decrease participants from the initial regression, the difference in accumulation attributable to genotype among Aβ- individuals was no longer significant. Further analysis revealed that in increase phases, Aβ accumulation was higher among noncarriers, indicating a genotype-related timeline shift. Finally, cognitive decline was analyzed across phases and was already evident in the Aβ-/increase phase. Our results encourage early interventions for ɛ4 carriers and imply that monitoring accumulating Aβ- individuals might help identify those at risk for cognitive decline. • Understanding amyloid beta trajectories is key for AD therapy trial designs. • APOE ɛ4 modulates onset of amyloid accumulation. • Confirmation of different accumulation phases in individuals without dementia. • Importance of trajectory clustering for patient selection. • Cognitive decline in amyloid normal individuals with high accumulation. [ABSTRACT FROM AUTHOR]

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE *2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aβ PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aβ in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aβ (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aβ differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets. • APOE*4 is associated with Aβ in non-Hispanic white, but not African American, participants • There were no racialized group differences in associations of APOE*4 with tau • There were no racialized group differences in associations of APOE*2 with Aβ and tau [ABSTRACT FROM AUTHOR]

INTRODUCTION: While observational research suggests a protective role for nutrition in brain aging, intervention studies remain inconclusive. This failing translation from observational to interventional research may result from overlooking nutrient interactions. METHODS: We developed a nutrient status index capturing the number of suboptimal statuses of omega‐3 fatty acids, homocysteine, and vitamin D (range 0 to 3). We associated this index with dementia incidence in a subsample (age ≥ 50 years) of the Framingham Heart Study Offspring cohort. RESULTS: Among 968 participants, 79 developed dementia over 15.5 years (median follow‐up). Each point increase in nutrient status index was associated with a 50% higher risk of dementia (hazard ratio [HR] = 1.50; 95% confidence interval [CI] = 1.16, 1.96). Participants with three high‐risk statuses had a four‐fold increased risk of dementia compared to participants without high‐risk status (HR = 4.68; 95% CI = 1.69, 12.94). DISCUSSION: Concurrent nutrient deficiencies are associated with the risk of dementia. The potential of optimizing nutritional status to lower dementia risk warrants further study. Highlights: Nutrition and dementia research calls for multiple‐nutrient approaches.We studied combined suboptimal statuses of omega‐3 polyunsaturated fatty acids, homocysteine, and vitamin D.Suboptimal status of the three nutrients was associated with dementia risk.The risk estimate was larger than for other factors (ie, diabetes, apolipoprotein E ε4 carrier).Future studies should assess the effect of improving nutrient status on dementia risk. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid‐related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ‐801/valiltramiprosate, an oral brain‐penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double‐blind, placebo‐controlled, 78‐week study of ALZ‐801 administered as 265 mg twice per day tablets, enrolled 50‐ to 80‐year‐old homozygotes with Mini‐Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating–Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug–placebo difference on the Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating–Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease‐modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ‐801 has the potential to be the first effective and safe anti‐amyloid treatment for the high‐risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo‐controlled, 78‐week study is designed to evaluate the efficacy and safety of ALZ‐801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini‐Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13‐item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating–Sum of Boxes, Amsterdam‐Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ‐801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain. METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40% male; and 25% apolipoprotein E (APOE) ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini–Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia. RESULTS: Higher plasma levels of sphingomyelin‐d18:1/16:0 (SM‐16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin‐d18:1/22:0 (SM‐22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM‐16 (hazard ration [HR] = 1.24 [95% confidence interval [CI]: 1.08–1.44]) and ceramide‐d18:1/16:0 (Cer‐16) (HR = 1.26 [95% CI: 1.10–1.45]) were associated with higher risk of incident dementia. DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk. Highlights: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline. [ABSTRACT FROM AUTHOR]

Introduction: We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. Methods: This population‐based study included 1191 dementia‐free participants (age ≥60 years) in the MIND‐China MRI Substudy (2018–2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Results: Greater BG‐EPVS load was associated with lower z‐scores in memory, verbal fluency, and global cognition (p < 0.05); these associations became non‐significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs). Overall, CSO‐EPVS load was not associated with cognitive z‐scores (p > 0.05); among apolipoprotein E (APOE) ‐ε4 carriers, greater CSO‐EPVS load was associated with lower verbal fluency z‐score, even when controlling for other CSVD markers (p < 0.05). Discussion: The associations of BG‐EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers. HIGHLIGHTS: The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)‐EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)‐EPVS load is associated with poorer verbal fluency. [ABSTRACT FROM AUTHOR]

Introduction: Depression and its components significantly impact dementia prediction and severity, necessitating reliable objective measures for quantification. Methods: We investigated associations between emotion‐based speech measures (valence, arousal, and dominance) during picture descriptions and depression dimensions derived from the geriatric depression scale (GDS, dysphoria, withdrawal‐apathy‐vigor (WAV), anxiety, hopelessness, and subjective memory complaint). Results: Higher WAV was associated with more negative valence (estimate = ‐0.133, p = 0.030). While interactions of apolipoprotein E (APOE) 4 status with depression dimensions on emotional valence did not reach significance, there was a trend for more negative valence with higher dysphoria in those with at least one APOE4 allele (estimate = –0.404, p = 0.0846). Associations were similar irrespective of dementia severity. Discussion: Our study underscores the potential utility of speech biomarkers in characterizing depression dimensions. In future research, using emotionally charged stimuli may enhance emotional measure elicitation. The role of APOE on the interaction of speech markers and depression dimensions warrants further exploration with greater sample sizes. Highlights: Participants reporting higher apathy used more negative words to describe a neutral picture.Those with higher dysphoria and at least one APOE4 allele also tended to use more negative words.Our results suggest the potential use of speech biomarkers in characterizing depression dimensions. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. Methods: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. Results: PTSD symptoms (B = 0.50–0.52, p < 1E-250) and probable TBI (B = 0.05–0.19, p = 1.51E-07 – 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13–1.21), APOE ε4 (HR = 1.73–2.05) and SCC (HR = 1.18–1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). Conclusions: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors. [ABSTRACT FROM AUTHOR]

Background: The soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) is considered a biomarker of microglia activity. The objective of this study was to investigate the trajectory of CSF sTREM2 levels over time and examine its association with sex. Methods: A total of 1,017 participants from the Alzheimer's Disease Neuroimaging Initiative Study (ADNI) with at least one CSF sTREM2 record were included. The trajectory of CSF sTREM2 was analyzed using a growth curve model. The association between CSF sTREM2 levels and sex was assessed using linear mixed-effect models. Results: CSF sTREM2 levels were increased with age over time (P < 0.0001). No significant sex difference was observed in sTREM2 levels across the entire sample; however, among the APOE ε4 allele carriers, women exhibited significantly higher sTREM2 levels than men (β = 0.146, P = 0.002). Conclusion: Our findings highlight the association between CSF sTREM2 levels and age-related increments, underscoring the potential influence of aging on sTREM2 dynamics. Furthermore, our observations indicate a noteworthy association between sex and CSF sTREM2 levels, particularly in individuals carrying the APOE ε4 allele. [ABSTRACT FROM AUTHOR]

Background and aim: Diabetes raises the risk of dementia, mortality, and cognitive decline in the elderly, potentially because of hereditary variables such as APOE. In this study, we aim to evaluate Diabetes mellitus and the risk of incident dementia in APOE ɛ4 carriers. Method: We thoroughly searched PubMed (Medline), Scopus, and Google Scholar databases for related articles up to September 2023. The titles, abstracts, and full texts of articles were reviewed; data were extracted and analyzed. Result: This meta-analysis included nine cohorts and seven cross-sectional articles with a total of 42,390 population. The study found that APOE ɛ4 carriers with type 2 diabetes (T2D) had a 48% higher risk of developing dementia compared to non-diabetic carriers (Hazard Ratio;1.48, 95%CI1.36–1.60). The frequency of dementia was 3 in 10 people (frequency: 0.3; 95%CI (0.15–0.48). No significant heterogeneity was observed. Egger's test, which we performed, revealed no indication of publication bias among the included articles (p = 0.2). Conclusion: Overall, diabetes increases the risk of dementia, but further large-scale studies are still required to support the results of current research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aβ and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals using two different proteomic technologies—tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 (APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aβ and tau. Editor's summary: The use of fluid biomarkers to stratify patients and monitor treatment response can facilitate the development of therapeutics for Alzheimer's disease (AD). To extend the AD marker toolkit, Dammer et al. established an integrated cerebrospinal fluid (CSF) proteomic network and showed that interconnected groups of proteins (modules) were associated with distinct disease aspects such as Aβ and tau pathology, cognitive dysfunction, or APOE E4 status. The M20 glycolysis/redox homeostasis module was elevated in AD and correlated with cognitive dysfunction. M20 was reduced after atomoxetine treatment in CSF from patients participating in a clinical trial. Together, these results could provide a useful resource for AD biomarker development. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE) is involved in cholesterol transport among cells and also plays an important role in amyloid formation, co-depositing with amyloid fibrils in various types of amyloidosis. Although the in vivo amyloidogenicity of ApoE has not been previously demonstrated, this study provides evidence of ApoE amyloidogenicity in leopard geckos (Eublepharis macularius), belonging to the class Reptilia. Histologically, amyloid deposits were localized within cholesterol granulomas and exhibited positive Congo red staining, with yellow to green birefringence under polarized light. On mass spectrometry-based proteomic analysis, ApoE was detected as a dominant component of amyloid; of the full length of the 274 amino acid residues, peptides derived from Leu185-Arg230 were frequently detected with non-tryptic truncations. Immunohistochemistry with anti-leopard gecko ApoE antibody showed positive reactions of amyloid deposits. These results show that ApoE is an amyloid precursor protein within the cholesterol granulomas of leopard geckos. Although further investigations are needed, the C-terminal region of ApoE involved in amyloid formation is a lipid-binding region, and there should be a relationship between amyloidogenesis and the development of cholesterol granulomas in leopard geckos. This study provides novel insights into the pathogenesis of ApoE-related diseases. [ABSTRACT FROM AUTHOR]

Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer’s disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human-induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research. [ABSTRACT FROM AUTHOR]

Background: Whether the relationships between ABO blood genotypes (AA, AO, BB, BO, AB, and OO) and dementia are modified by gender and APOE status has been unclear. Methods: We used data from the UK Biobank, a population-based cohort study of 487,425 individuals. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) between ABO genotypes and risk of dementia. Multivariable linear regression models were used to estimate the relationship between ABO genotypes and MRI-based brain indices. Results: Overall, 487,425 participants were included at baseline. After 34 million person-years follow up, 7,548 patients developed all-cause dementia. Before stratifying by sex and APOE status, compared to OO genotype, BB genotype was associated with increased risk of all-cause dementia (1.36, 1.03–1.80) and other types dementia (1.65, 1.20–2.28). After stratifying by sex, only in males, BB genotype was associated with higher risk of all-cause dementia (1.44, 1.02–2.09) and other types of dementia (1.95, 1.30–2.93). AB genotype in males was also associated with increased AD (1.34, 1.04–1.72). After further stratifying by APOE e4 status, BB genotype with two APOE e4 alleles showed even stronger association with all-cause dementia 4.29 (1.57, 11.72) and other types dementia (5.49, 1.70–17.69) in males. Also in males, AA genotype with one APOE e4 was associated with increased risks of all-cause dementia (1.27, 1.04–1.55), AD (1.45, 1.09–1.94) and other types dementia (1.40, 1.08–1.81). Linear regression models showed that in both sexes with APOE e4, AA genotype was associated with reduced total grey matter volume. Conclusion: Sex and APOE e4 carrier status modified the association between ABO genotypes and risk of dementia. In males, BB genotype was consistently associated with increased risk of dementia, especially in those with two APOE e4 alleles. Also, in males with one APOE e4, AA genotype might be linked to higher risk of dementia. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. Methods: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. Results: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. Conclusions: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD. [ABSTRACT FROM AUTHOR]

This article explores the role of underrepresented populations in polygenic risk scores (PRS) for predicting the risk of neurodegenerative diseases. Neurodegenerative diseases, such as Alzheimer's and Parkinson's, have a significant impact on global health, particularly in underrepresented populations. However, most genetic research and GWAS studies have focused on populations of European ancestry, leading to a lack of diversity in the data. PRS, which combines genetic susceptibility variants, can be used to estimate an individual's risk of developing a disease. However, there are challenges in applying PRS to underrepresented populations due to differences in genetic architecture and ancestry. Efforts are being made to improve the transferability of PRS across diverse populations and incorporate ancestry-specific genetic information. The text discusses the importance of including underrepresented populations (URPs) in genetic research, particularly in the context of polygenic risk scores (PRS) and genome-wide association studies (GWAS). It highlights the increasing efforts to include URPs in genomic studies through the establishment of biobanks and disease-specific consortia in various regions, such as Asia, Africa, Latin America, and Europe. The inclusion of URPs is crucial for understanding disease etiology, identifying population-specific risk variants, and improving disease prediction accuracy. The text also emphasizes the need for standardized databases that represent the global population and the integration of environmental and lifestyle factors in risk prediction models. The given document is a list of references for various scientific articles related to genetic research on neuro [Extracted from the article]

Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory–secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE−/−) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer's disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer's disease. While a correlation between olfactory dysfunction and Alzheimer's disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer's disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer's disease including amyloid-β protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction. [ABSTRACT FROM AUTHOR]

The linkage between low-density lipoprotein receptor-related protein (LRP)1-mediated metabolism of apolipoprotein (apo) E-containing lipoproteins (apoE-LP) and the lipopolysaccharide (LPS)-induced inflammatory response contributes to the pathogenesis of sepsis; however, the underlying mechanisms are unclear. Therefore, in this study, the effects of apoE-LP and their constituents on the mRNA expression of interleukin (IL)-6 and LRP1 were evaluated using a culture system of human fibroblasts supplemented with LPS and apoE-containing emulsion particles (apoE-EP). The affinity of apoE-LP for LPS was examined using the interaction between fluorescence-labeled LPS and serum lipoprotein fractions. LPS-induced inflammation significantly upregulated the mRNA expression of IL-6 and LRP1. This upregulation was markedly suppressed by pre-incubation of LPS with apoE-EP or its constituents (apoE or EP). The suppressive effect of apoE-EP on IL-6 upregulation was attenuated in the presence of lactoferrin, an inhibitor of LRP1. The prepared apoE-EP and serum triglyceride-rich lipoproteins showed significant affinity for LPS. However, these affinities appeared to be lower than expected based on the extent to which IL-6 upregulation was suppressed by pre-incubation of LPS with apoE-EP. Overall, these results indicate that LPS-induced inflammation may be regulated by 1) the LPS-neutralizing effect of apoE-LP, 2) anti-inflammatory effect of apoE, and 3) LRP1-mediated metabolic pathways. [ABSTRACT FROM AUTHOR]

GV1001, an anticancer vaccine, exhibits other biological functions, including anti-inflammatory and antioxidant activity. It also suppresses the development of ligature-induced periodontitis in mice. Porphyromonas gingivalis (Pg), a major human oral bacterium implicated in the development of periodontitis, is associated with various systemic disorders, such as atherosclerosis and Alzheimer's disease (AD). This study aimed to explore the protective effects of GV1001 against Pg-induced periodontal disease, atherosclerosis, and AD-like conditions in Apolipoprotein (ApoE)-deficient mice. GV1001 effectively mitigated the development of Pg-induced periodontal disease, atherosclerosis, and AD-like conditions by counteracting Pg-induced local and systemic inflammation, partly by inhibiting the accumulation of Pg DNA aggregates, Pg lipopolysaccharides (LPS), and gingipains in the gingival tissue, arterial wall, and brain. GV1001 attenuated the development of atherosclerosis by inhibiting vascular inflammation, lipid deposition in the arterial wall, endothelial to mesenchymal cell transition (EndMT), the expression of Cluster of Differentiation 47 (CD47) from arterial smooth muscle cells, and the formation of foam cells in mice with Pg-induced periodontal disease. GV1001 also suppressed the accumulation of AD biomarkers in the brains of mice with periodontal disease. Overall, these findings suggest that GV1001 holds promise as a preventive agent in the development of atherosclerosis and AD-like conditions associated with periodontal disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating disorder with a global prevalence estimated at 55 million people. In clinical studies administering certain anti-beta-amyloid (Aβ) antibodies, amyloid-related imaging abnormalities (ARIAs) have emerged as major adverse events. The frequency of these events is higher among apolipoprotein ε4 allele carriers (APOE4) compared to non-carriers. To reflect patients most at risk for vascular complications of anti-Aβ immunotherapy, we selected an APPswe/PS1dE9 transgenic mouse model bearing the human APOE4 gene (APPPS1:E4) and compared it with the same APP/PS1 mouse model bearing the human APOE3 gene (APOE ε3 allele; APPPS1:E3). Using histological and biochemical analyses, we characterized mice at three ages: 8, 12, and 16 months. Female and male mice were assayed for general cerebral fibrillar and pyroglutamate (pGlu-3) Aβ deposition, cerebral amyloid angiopathy (CAA), microhemorrhages, apoE and cholesterol composition, astrocytes, microglia, inflammation, lysosomal dysfunction, and neuritic dystrophy. Amyloidosis, lipid deposition, and astrogliosis increased with age in APPPS1:E4 mice, while inflammation did not reveal significant changes with age. In general, APOE4 carriers showed elevated Aβ, apoE, reactive astrocytes, pro-inflammatory cytokines, microglial response, and neuritic dystrophy compared to APOE3 carriers at different ages. These results highlight the potential of the APPPS1:E4 mouse model as a valuable tool in investigating the vascular side effects associated with anti-amyloid immunotherapy. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE−/−) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE−/− females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE−/− also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury. [ABSTRACT FROM AUTHOR]

Introduction: Atherosclerosis has become a worldwide medical burden. Our previous studies have shown that artemisinin (ART) had the capability to reduce atherosclerosis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are involved in the development of atherosclerosis. However, whether lncRNAs might participate in the mechanism through which artemisinin mitigates atherosclerosis has not been reported. Material and methods: Eight-week-old apolipoprotein E deficient (APOE-/-) mice were divided into two groups, one of which was treated with artemisinin. Red oil O staining was used to measure the sizes of the atherosclerotic lesions. We conducted deep sequencing to investigate lncRNA profiles in the aorta tissue in high-fat diet fed APOE knockdown mice with and without artemisinin treatment. CeRNA network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed through bioinformatics analysis. RT-PCR was used to validate the differentially expressed lncRNAs. Results: A total of 102 lncRNAs and 4,630 mRNAs were differentially expressed (p < 0.05) between the artemisinin treatment group and atherosclerosis model group. KEGG and GO analyses indicated that the categories metabolic process, specific amino acid degradation and PI3K-Akt signaling pathway are involved in the effects of artemisinin treatment in atherosclerosis (q < 0.05). LncRNA ENSMUST00000099676.4, ENSMUST00000143673.1, ENSMUST00000070085.5 and ENSMUST00000224554 might be engaged in the treatment mechanism through which artemisinin alleviates atherosclerosis. Conclusions: These findings indicated the possible mechanism and therapeutic role of lncRNAs in artemisinin treatment of atherosclerosis and provided a theoretical basis for the future application of artemisinin in patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

Hearing loss and diminished visual acuity are associated with poorer cognition, but the underlying mechanisms are not understood. The apolipoprotein (APOE) ε4 allelic variant may drive the associations. We tested whether APOE -ε4 allele count (0, 1, or 2) was associated with declines in memory, executive function, pure-tone hearing threshold averages, and pinhole-corrected visual acuity among participants in the Canadian Longitudinal Study on Aging (CLSA). Multivariable linear mixed regression models were utilized to assess associations between APOE -ε4 allele count and each of the outcome variables. For each main effects model, interactions between APOE -ε4 and sex and age group (45–54-, 55–64-, 65–74-, and 75–85 years) respectively, were analyzed. Significant associations were not observed in main effects models. Models including APOE- ε4 * age (but not APOE- ε4 * sex) interaction terms better fit the data compared to main effects models. In age group-stratified models, however, there were minimal differences in effect estimates according to allele count. APOE -ε4 allele count does not appear to be a common cause of sensory-cognitive associations in this large cohort. [ABSTRACT FROM AUTHOR]

The development of biomarkers for Alzheimer disease (AD) has led to the origin of suspected non-AD pathophysiology (SNAP) — a heterogeneous biomarker-based concept that describes individuals with normal amyloid and abnormal tau and/or neurodegeneration biomarker status. In this Review, we describe the origins of the SNAP construct, along with its prevalence, diagnostic and prognostic implications, and underlying neuropathology. As we discuss, SNAP can be operationalized using different biomarker modalities, which could affect prevalence estimates and reported characteristics of SNAP in ways that are not yet fully understood. Moreover, the underlying aetiologies that lead to a SNAP biomarker profile, and whether SNAP is the same in people with and without cognitive impairment, remains unclear. Improved insight into the clinical characteristics and pathophysiology of SNAP is of major importance for research and clinical practice, as well as for trial design to optimize care and treatment of individuals with SNAP. Suspected non-AD pathophysiology (SNAP) is a biomarker-based concept that describes individuals with normal amyloid and abnormal tau and/or neurodegeneration biomarker status. This Review discusses the origins of the SNAP construct, along with its prevalence, diagnostic and prognostic implications, and underlying neuropathology. Key points: Suspected non-Alzheimer disease (AD) pathophysiology (SNAP) is a heterogeneous biomarker-based concept describing individuals with a normal amyloid biomarker and abnormal tau and/or neurodegeneration biomarkers. SNAP is common in people with normal cognition (NC) or mild cognitive impairment (MCI) and is associated with a reduced frequency of the apolipoprotein E ε4 allele (a key genetic risk factor for AD) compared with individuals with abnormal amyloid biomarkers. Evidence shows that NC-SNAP is associated with a low risk of cognitive decline over 7 years, whereas MCI-SNAP is associated with an increased risk of developing clinical AD dementia. Cerebrospinal fluid (CSF) proteomics studies suggest a disturbance in amyloid metabolism and involvement of the blood–CSF barrier in people with MCI-SNAP. Neuropathological studies indicate that SNAP can represent early AD pathology, presumed AD-spectrum pathologies such as primary age-related tauopathy or non-AD pathologies that occur with increased frequency in AD, such as limbic-predominant age-related TAR DNA-binding protein 43 encephalopathy neuropathological change, argyrophilic grain disease or Lewy body disease. More sensitive biomarkers of amyloid pathology and novel biomarkers for non-AD pathologies are needed to identify the underlying cause of SNAP in vivo and provide appropriate treatments. [ABSTRACT FROM AUTHOR]

Aims: To investigate the roles of neurotrophic factors on cognition in patients with Alzheimer's disease (AD) carrying Apolipoprotein E (APOE) ε4. Methods: Totals of 173 patients with AD were divided into APOE ε4 carrier and non‐carrier groups, and their demographics, cognition, and neurotrophic factors in cerebrospinal fluid (CSF) were compared. Multiple linear regression analyses were performed to assess correlations among APOE ε4, neurotrophic factors and cognition. Mediation analyses were conducted to assess the sequential associations among APOE ε4, nerve growth factor (NGF), and cognition. Results: Global cognition and multiple domains were impaired in the APOE ε4 carrier group (all p < 0.05). NGF level in the APOE ε4 carrier group was lower than that in the non‐carrier group (p = 0.016). NGF level showed significant correlations with both global and multiple domains cognitions. Specifically, NGF mediated the association between APOE ε4 and Animal Fluency Test score (β, −0.45; 95% CI [−0.96, −0.07]; p < 0.001) and Trail Making Test‐A (time) (β, 0.15; 95% CI [0.01, 0.33]; p < 0.001). Conclusion: APOE ε4 is associated with cognitive impairment, and those carrying APOE ε4 have decreased NGF level in CSF. Declined NGF level is correlated with compromised cognition. NGF mediates APOE ε4‐associated cognitive impairment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. METHODS: We investigated differences in serum and brain metabolites between the early‐onset 5XFAD and late‐onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. Highlights: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease.Mouse models exhibit broad sex‐specific metabolic differences, similar to human study cohorts.The early‐onset 5XFAD mouse model primarily alters brain metabolites while the late‐onset LOAD1 model primarily changes serum metabolites.Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super‐Seniors. METHODS: Three hundred seventy plasma specimens from Super‐Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD‐X analyzer using commercial Neurology 4‐plex E and phosphorylated tau (p‐tau)181 assays. RESULTS: Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non‐carriers. No significant differences were found between APOE ε4 carriers and non‐carriers regarding age, sex, or Mini‐Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p‐tau181 and glial fibrillary acidic protein were higher compared to non‐APOE ε4 carriers. After adjusting for demographic variables, p‐tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. DISCUSSION: APOE ε4 genotype modifies plasma p‐tau181 concentration in seniors resilient to age‐related clinical disease, suggesting that some Super‐Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. Highlights: Healthy seniors enable identification of associations that may be masked by disease.Plasma phosphorylated tau (p‐tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors.APOE should be accounted for when interpreting p‐tau181, regardless of disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Evaluating whether genetic susceptibility modifies the impact of lifestyle‐related factors on dementia is critical for prevention. METHODS: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non‐carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle‐based prevention may be effective whatever the genetic susceptibility to dementia. [ABSTRACT FROM AUTHOR]

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development. The isodendritic core is a group of neuromodulatory nuclei with diffuse projections. Here the authors describe associations between the microstructural integrity of the isodendritic core and whole-brain white matter in humans, and its relationship to Apolipoprotein-E4 carrier status. [ABSTRACT FROM AUTHOR]

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics. Here the authors connect inherited Apolipoprotein E genotype with the risk of developing Alzheimer's disease by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Amyloid-beta. [ABSTRACT FROM AUTHOR]

Early detection of Alzheimer's disease (AD) represents an unmet clinical need. Beta-amyloid (Aβ) plays an important role in AD pathology, and the Aβ42/40 peptide ratio is a good indicator for amyloid deposition. In addition, variants of the apolipoprotein E (APOE) gene are associated with variable AD risk. Here, we describe the development and validation of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for plasma Aβ40 and Aβ42 quantitation, as well as apolipoprotein E (ApoE) proteotype determination as a surrogate for APOE genotype. Aβ40 and Aβ42 were simultaneously immunoprecipitated from plasma, proteolytically digested, and quantitated by LC-MS/MS. ApoE proteotype status was qualitatively assessed by targeting tryptic peptides from the ApoE2, ApoE3, and ApoE4 proteoforms. Both assays were validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Within-run precision was 1.8%–4.2% (Aβ40), 1.9%–7.2% (Aβ42), and 2.6%–8.3% (Aβ42/40 ratio). Between-run precision was 3.5%–5.9% (Aβ40), 3.8%–8.0% (Aβ42), and 3.3%–8.7% (Aβ42/40 ratio). Both Aβ40 and Aβ42 were linear from 10 to 2500 pg/mL. Identified ApoE proteotypes had 100% concordance with APOE genotypes. We have developed a precise, accurate, and sensitive high-throughput LC-MS/MS assay for plasma Aβ40, Aβ42, and proteoforms of ApoE. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) poses a major obstacle in the treatment of all types of central nervous system (CNS) diseases. Small interfering RNA (siRNA) offers in principle a promising therapeutic approach by downregulating disease-related genes via RNA interference. However, the BBB is a formidable barrier for macromolecules such as nucleic acids. In an effort to develop a brain-targeted strategy for siRNA delivery systems formed by electrostatic interactions with cationic polymers (polyplexes (PXs)), we investigated the suitability of the well-known surfactant-based approach for Apolipoprotein E (ApoE)-functionalization of nanoparticles (NPs). The aim of this present work was to investigate if ApoE coating of siRNA PXs formed with cationic branched 25-kDa poly(ethyleneimine) (b-PEI) and nylon-3 polymers without or after precoating with polysorbate 80 (PS 80) would promote successful delivery across the BBB. We utilized highly hydrophobic NM0.2/CP0.8 nylon-3 polymers to evaluate the effects of hydrophobic cyclopentyl (CP) subunits on ApoE binding efficacy and observed successful ApoE binding with and without PS 80 precoating to the nylon-3 but not the PEI polyplexes. Accordingly, ApoE-coated nylon-3 polyplexes showed significantly increased uptake and gene silencing in U87 glioma cells but no benefit in vivo. In conclusion, further optimization of ApoE-functionalized polyplexes and more sophisticated in vitro models are required to achieve more successful in vitro-in vivo translation in future approaches. [ABSTRACT FROM AUTHOR]

2-ethylhexyl diphenyl phosphate (EHDPP) is an aryl organophosphorus flame retardant, which is ubiquitously found in various environmental matrices. While previous in vitro studies have emphasized the negative impact of EHDPP on lipid metabolism, there remains a dearth of in vivo research exploring its potential toxic effects and underlying mechanisms. In the present study, zebrafish (Danio rerio) embryos (<2 hpf) were exposed to environmentally relevant concentrations (0, 1, 10, 100, 250 and 500 µg ⋅ L-1) for 5 days. Results showed that 100, 250 and 500 µg ⋅ L-1 EHDPP may lead to developmental toxicity, evidenced by the increased malformation rate, reduced hatching rate, heart rate, survival rate and body length, in comparison with the control. The levels of total cholesterol and triglycerides were significantly reduced in 500 µg ⋅ L-1 EHDPP group compared to the control, suggesting that EHDPP caused disorders of lipid metabolism. EHDPP resulted in a notable reduction in the concentrations of ATP, SOD, and GSH, along with an elevation in ROS levels, suggestive of mitochondrial dysfunction triggered by EHDPP. Upon further analysis, it was revealed that the transcription of the 18rs-rrn gene was significantly reduced, while the expressions of genes involved in mitochondrial division (including mitochondrial fission protein 1 (fis1) and dynamin-related protein (drp1)), fusion (optic atrophy 1 (opa1)), and autophagy (PTEN-induced putative kinase 1 (pink1) and FUN14 domain containing 1 (fundc1)) were notably upregulated, which may partially account for the mitochondrial dysfunction. Genes involved in lipid biosynthesis including acid synthetase (fas) and apolipoprotein E (apoe) genes were significantly downregulated, whereas genes related to lipid metabolism such as peroxisome proliferators-activated receptors (pparα and pparβ) and acyl-CoA oxidase 1 (acox1) were upregulated. These results implied that EHDPP may disturb fatty acid oxidation and lipid synthesis in zebrafish larvae which might result from mitochondrial dysfunction. In conclusion, our study found that EHDPP may induce lipid metabolism disorders. For the first time, we have demonstrated mitochondrial dysfunction in vivo resulting from the effects of EHDPP, potentially offering novel insights into the toxicity elicited by this compound. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, including in Pakistan. Cardiovascular problems linked with T2DM have a significant impact on individuals and society. The goal of this study is to investigate the relationship between Apolipoprotein E (ApoE) genotypes, dyslipidemia, and cardiovascular complications such as ischemic heart disease (IHD) and stroke. Methods: This study was carried out on 260 subjects divided into controls and diabetics. The diabetics were further divided into four subgroups such as D1: diabetics without cardiovascular issues, D2: diabetics with heart disease, D3: diabetics with stroke, and D4: diabetics with both heart disease and stroke. Anthropometric parameters (age, BMI) and risk factors (smoking, diabetes duration, hypertension) were assessed in all groups. Serum levels of TC, TG, LDL, HDL, VLDL, creatinine, BSF, and HbA1c were also measured. Apolipoprotein E gene polymorphism was determined using PCR-RFLP. Results: Hypertension, BMI, and dyslipidemia are defined as elevated levels of total cholesterol, triglycerides, LDL, and VLDL, and decreased levels of HDL. Uncontrolled hyperglycemia (elevated fasting blood sugar and glycated hemoglobin) in T2DM was linked to vascular complications such as IHD and stroke. Hypertension was prevalent in 79.3% of the population. Stage 2 hypertension was more prevalent in all age groups. It was also noted that common genotypes in the Pakistani population are 3/3, 4/4, 2/3, and 3/4. The frequency of genotypes 3/4 and 2/3 is highest in diabetics with stroke. Genotype 3/3 is present frequently in diabetics with IHD/stroke and patients with both these complications. However, genotype 4/4 is most frequently found in diabetics with IHD. Conclusions: It is concluded that BMI, hypertension, hyperglycemia, atherosclerosis, and dyslipidemia are linked with cardiovascular complications of type 2 diabetes. Apolipoprotein E gene polymorphism is associated with cardiovascular disease in patients with diabetes by affecting the lipid profile. [ABSTRACT FROM AUTHOR]