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As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimers disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimers Association convened multidisciplinary researchers at the AAIC Advancements: APOE conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoEs multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimers disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

Although most children with cerebral malaria fully recover, more than a fifth of the survivors develop post-discharge neurodevelopmental sequelae suggestive of advanced neuronal injury. However, the cerebral molecular processes initiating neurological dysfunction in cerebral malaria are still debatable. In this article, we explore available data and hypothesise that cerebral malaria might be linked to APOE-mediated amyloidosis, one of the pathological processes associated with Alzheimer's disease. If our hypothesis is tested and found to be true, it could have far-reaching implications for what we know about cerebral malaria pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The apolipoprotein E ε4 (APOE ε4) status has a controversial role in predicting Alzheimer's disease (AD) factors. This meta-analysis assessed AD event risk in patients with APOE ε4 status. Materials and methods: The relevant English-language articles were identified by searching the Cochrane Library, EMBASE, and PubMed databases. The prognostic significance of APOE ε4 status in AD patients was examined on the basis of pooled hazard ratios (HRs). Results: A total of 22 studies published after 1987, including 571,800 patients, were included. Consequently, APOE ε4 status was a risk factor for disease-free survival (DFS, HR = 2.033; 95% confidence interval [CI] = 1.589–2.602; P = 0.000; I 2 = 93.1%) in patients with AD. Additionally, subgroup analysis suggested that the ROC curve was the main risk factor among patients with AD. Conclusions: AD patients with different events are managed via different methods; however, the present meta-analysis suggests an increased risk of AD events in patients with different APOE ε4 statuses. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E4 (ApoE4) is associated with an increased risk of Alzheimer's disease (AD), depression, and anxiety, which were reported to improve after the administration of metformin. However, sex influence on the effect of ApoE4 and metformin on cognition and mental health is poorly understood. Methods: ApoE3-TR and apoE4-TR mice of both sexes were randomly assigned to the normal saline and metformin groups from 13 months to 18 months of age. Behavior tests (MWM, EPM, OFT, TST, FST) were conducted to assess cognition, anxiety, and depression-like behaviors. The mice's blood glucose was also recorded. Results: Male aged apoE4-TR mice are more vulnerable to cognitive decline than females. Metformin improves the spatial memory of female, but not male apoE3-TR mice and female apoE4-TR mice while aggravating the cognitive impairment of male apoE4-TR mice. The anxiety-like phenotypes in male apoE4-TR mice are more severe than in male apoE3-TR mice, while metformin ameliorates the anxiety-like behaviors in the male apoE4-TR mice but not in male apoE3-TR mice. In addition, metformin alleviates depression-like behaviors in male and female apoE4-TR mice. The hypoglycemic effect of metformin is insignificant in both male and female apoE4-TR mice. Conclusions: Male sex exacerbates APOE4-related cognitive impairment and anxiety in aged mice and is insensitive to the cognition improvement effect of metformin in the aged apoE3 mice. Male sex with APOE4 may experience more severe cognitive impairment after treatment with metformin while sensitive to the anti-anxiety effects of metformin. These findings identify sex-specific effects on ApoE4-based dementia, anxiety prevention, and therapy, emphasizing the importance of further sex dimension analyses in vivo and clinical studies. Plain language summary: The apolipoprotein E4 (APOE4) gene increases the risk of Alzheimer's disease, depression, and anxiety. The present study examined how ApoE4 and a hypoglycemic drug, metformin, affected male and female mice's cognition and mental health. The mice were carriers of the APOE3 gene (which is less risky) or the APOE4 gene. They were given normal saline or metformin from 13 to 18 months of age. We found that: (1) Male apoE4 mice showed more cognitive decline than female apoE4 mice as they aged. (2) Metformin improved the spatial cognition of female apoE3 mice but not male apoE3 mice or female apoE4 mice. Metformin worsened the cognitive problems of male apoE4 mice. (3) Male apoE4 mice showed more anxiety-like behavior than male apoE3 mice. However, metformin reduced the anxiety in male apoE4 mice but not in male apoE3 mice. (4) Metformin reduced depression-like phenomenon in both male and female apoE4 mice. (5) ApoE4 reduces the ability of metformin to lower blood sugar in mice, regardless of gender. These findings highlight the importance of considering sex differences in studies of ApoE4-related dementia, anxiety, and treatment. Highlights: ApoE4 could aggravate memory decline and anxiety-like phenotype in male aged mice but not females. Metformin was observed to have a sex-dependent improvement in the spatial memory of aged apoE3-TR mice. Metformin leads to lower cognitive performance in male apoE4-TR mice and has anti-anxiety effects on them. ApoE4 blunts metformin's hypoglycemic impact in aged male and female mice. [ABSTRACT FROM AUTHOR]

Background: Changes in the Alzheimer's disease-related apolipoprotein genes expression, occurring parallel with brain ischemia-induced neurodegeneration in the hippocampal CA3 area, may be crucial for the development of memory loss and dementia. Objective: The aim of the study was to investigate changes in genes expression of apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and clusterin (CLU) in CA3 area post-ischemia with survival of 2 years. Methods: The gene expression was evaluated with the use of an RT-PCR protocol after 2, 7, and 30 days and 6, 12, 18, and 24 months post-ischemia. Results: The expression of the APOA1 gene (encoding apolipoprotein A1) was below the control values at 2 days, 6 and 12 months while at 7 and 30 days and 18 and 24 months post-ischemia this gene expression exceeded the control values. In the case of the CLU gene (encoding clusterin) expression, it was above the control values at all times post-ischemia. Similar expression was observed for the APOE gene (encoding apolipoprotein E) except on day 7 after ischemia where its expression was below the control value. Conclusions: The results seem to indicate that the observed changes in the gene expression may reflect the activation and inhibition of a variety of processes involved in ischemia-induced neurodegeneration. The enhanced expression of APOA1 and CLU genes may be associated with induction of neuroprotective mechanisms while increased expression of the APOE gene may produce detrimental effects. [ABSTRACT FROM AUTHOR]

Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer's disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35–65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is a multigenic condition influenced by both nature and nurture (60% to 40%). Prognosis of CAD is based on familial patterns. This study examined and analyzed the susceptibility of CAD to genetic variants in various Pakistani families. A total of 50 families, 308 participants (79 affected and 229 unaffected were genotyped for NOS3 (rs1799983, rs2070744), PON1 (rs662), LPA-PLA2 (rs105193, rs1805017), APOE (rs429358, rs7412), PCSK9 (rs505151), MEF2A (rs325400), TNF (rs1800629) and LDLR (rs1122608, rs2228671) genes. The family-based association in CAD associated genes SNPs were NOS3 (rs1799983), PON1 (rs662), LPA-PLA2 (rs1805017), MEF2A (rs325400), and LDLR (rs1122608, rs222867) showed transmission within families p≤ 0.05 whereas NOS3 (rs2070744), APOE (rs429358, rs7412) and TNF (rs1800629) showed no association TDT asymptotic p-value >0.05. In DFAM and QFAM test NOS3 (rs1799983), PON1 (rs662), MEF2A (rs325400), and LDLR (rs1122608, rs222867) showed positive association p≤ 0.05 in both whereas NOS3 (rs2070744), APOE (rs429358, rs7412), LPA-PLA2 (rs1805017) and TNF (rs1800629) showed low risk of transmission asymptotic p-value >0.05 in DFAM but NOS3(rs2070744), APOE(rs7412), LPA-PLAG2(rs1805017) also showed association p≤ 0.05 whereas APOE (rs429358) and TNF (rs1800629) showed no association EMP1 p-value >0.05 in QFAM. In linkage analysis Chromosome 6 (Position 70.810): LOD = 3.16, Chromosome 7 (Position 107.190): LOD = 3.16, and chromosome 19 (Position 31.470): LOD = 3.90 also showed significant association with disease as p < 0.05. This discovery enhances the understanding about genetic variants of CAD and also facilitates early detection, targeted interventions, pattern of inheritance in population. This ultimately improving patient outcomes and guiding future research to highlight its significance as a potential diagnostic marker. [ABSTRACT FROM AUTHOR]

Background: APOE gene polym orphisms have been linked to Alzheimer's disease and coronary heart diseases. However, their relationship with lung adenocarcinoma (LUAD) remains uncertain. Methods: This study analyzed a cohort of 600 individuals comprising 200 LUAD patients in the lung cancer group and 400 healthy individuals as controls. APOE gene variants were identified through Sanger sequencing. Statistical analyses were conducted to assess intergroup differences, and comparisons of lipid profiles were performed across individuals carrying different APOE alleles. Results: The APOE ϵ2 allele had been significantly more frequently occurring in the LUAD group than in the control group (15.5% vs. 7%, P <0.001). APOE ϵ2/ϵ2 and ϵ2/ϵ3 genotypes increased susceptibility to LUAD by 3.78-fold and 3.22-fold. The APOE ϵ2/ϵ3 genotype increased the risk of early-stage LUAD by 2.36-fold and advanced-stage LUAD by 4.05-fold. Individuals with the APOE ϵ2/ϵ2 genotype had a 3.22-fold higher susceptibility to moderately differentiated and a 6.8-fold higher susceptibility to poorly differentiated LUAD. Patients with the ϵ2 allele in LUAD exhibited disrupted lipid metabolism, characterized by reduced HDL, TC, and FFA levels, along with increased ApoB, particularly in advanced and poorly differentiated cancer stages. Conclusion: Individuals carrying the ϵ2 allele have an increased susceptibility to developing LUAD, accompanied by disrupted lipid metabolism. Additionally, the APOE ϵ2/ϵ2 and ϵ2/ϵ3 genotypes are associated with an increased risk of developing advanced and poorly differentiated LUAD. [ABSTRACT FROM AUTHOR]

The combination of alcohol and a low-carbohydrate, high-protein, high-fat atherogenic diet (AD) increases the risk of lethal arrhythmias in apolipoprotein E/low-density lipoprotein receptor double-knockout (AL) mice with metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigates whether left ventricular (LV) myocardial interstitial fibrosis (MIF), formed during the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributes to this increased risk. Male AL mice were fed an AD with or without ethanol for 16 weeks, while age-matched AL and wild-type mice served as controls. Liver and heart tissues were analyzed, and susceptibility to lethal arrhythmias was assessed through histopathology, fluorescence immunohistochemistry, RNA-Seq, RT-PCR, and lethal arrhythmia-evoked test. Ethanol combined with an AD significantly induced LV MIF in MASH-affected AL mice, as shown by increased fibrosis-related gene expression, Sirius-Red staining, and elevated collagen 1a1 and 3a1 mRNA levels, alongside a higher incidence of lethal arrhythmias. Cardiac myofibroblasts exhibited sympathetic activation and produced elevated levels of fibrosis-promoting factors. This study highlights the role of cardiac myofibroblasts in LV MIF, contributing to an increased incidence of lethal arrhythmias in MASH-affected AL mice fed ethanol and AD, even after the alcohol was fully metabolized on the day of consumption. [ABSTRACT FROM AUTHOR]

Transmembrane and coiled‐coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age‐matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2‐immunoreactive and methoxy‐X04‐positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain‐derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD. [ABSTRACT FROM AUTHOR]

This article investigates the intricate associations between apolipoprotein E (APOE) gene alleles variation, insulin resistance (IR) and amyloid‐β aggregation in cardiovascular disease (CVD) patients. A cohort of 250 patients exhibiting the symptoms of CVD and 50 control subjects participated in this study. After applying the stringent inclusion and exclusion criteria, the diseased group was further stratified into three categories: CVD+ (Alzheimer's disease) AD, CVD + (diabetes mellitus) DM and CVD + DM + AD. Blood samples were collected from all recruited participants for the biochemical analyses of lipid profile, glycaemic status, liver function enzymes, inflammatory and oxidative stress biomarkers. Tetra amplification‐refractory mutation system‐polymerase chain reaction (ARMS‐PCR) was employed for APOE gene analysis. Biochemical evaluations revealed the significant elevations in the serum levels of glucose, liver enzymes, interleukin‐6 (IL‐6), cholesterol, low‐density lipoproteins (LDL), triglycerides (TG) and malondialdehyde (MDA) in CVD + DM + AD group. Conversely, the serum levels of insulin, HDL and hexokinase decreased in CVD + DM + AD group compared to the controls and other CVD groups. Tetra ARMS‐PCR results indicated a higher percentage of the risk allele in CVD + DM + AD group when compared with the other groups. Our study elucidates the multifaceted cardiovascular risk factors contributing to IR and AD in CVD patients. Age‐related risk factors, prevalence of APOE risk alleles and the impact of statin use on AD incidences were identified. These findings underscore the need for tailored preventive measures, particularly in APOEε4 and ε3/ε4 carriers with CVD. Further studies should delve into the knowledge‐based protocols to comprehend the underlying mechanisms. Focusing on the therapeutic targets to prevent or delay DM and AD progression in CVDs, especially in APOEε4 carriers, is essential. [ABSTRACT FROM AUTHOR]

Dysbetalipoproteinemia (DBL) is a combined dyslipidemia associated with an increased risk of atherosclerotic cardiovascular diseases mostly occurring in ε2ε2 subjects and infrequently in subjects with rare APOE variants. Several algorithms have been proposed to screen DBL. In this work, we compared the diagnostic performances of nine algorithms including a new one. Patients were divided into 3 groups according to their APOE genotype: ε2ε2 ("ε2ε2", n=49), carriers of rare variants ("APOEmut", n=20) and non-carriers of ε2ε2 nor APOE rare variant ("controls", n=115). The algorithms compared were those from Fredrickson, Sniderman, Boot, Paquette, De Graaf, Sampson, eSampson, Bea and ours, the "Hospices Civils de Lyon (HCL) algorithm". Our gold standard was the presence of a ε2ε2 genotype or of a rare variant associated with triglycerides (TG) >1.7 mmol/L. A replication in the UK Biobank and a robustness analysis were performed by considering only subjects with both TG and low-density lipoprotein-cholesterol (LDLc) >90th percentile. Total cholesterol (TC)/ApoB and NHDLC/ApoB are the best ratios to suspect DBL. In ε2ε2, according to their likelihood ratios (LR), the most clinically efficient algorithms were the HCL, Sniderman and De Graaf's. In APOEmut, Sniderman's algorithm exhibited the lowest negative LR (0.07) whereas the HCL's exhibited the highest positive LR (29). In both cohorts, the HCL algorithm had the best LR. We proposed a powerful algorithm based on ApoB concentration and the routine lipid profile, which performs remarkably well in detecting ε2ε2 or APOE variant-related DBL. Additional studies are needed to further evaluate algorithms performances in DBL carriers of infrequent APOE variants. [ABSTRACT FROM AUTHOR]

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer's disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Apolipoprotein E (ApoE) plays a crucial role in lipid homeostasis, predominantly expressed in astrocytes and to a lesser extent in microglia within the central nervous system (CNS). While the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), its precise role in AD pathogenesis remains elusive. Apoe -knockout (Apoe -ko) mice, mice expressing human APOE4 , and human APOE4 carriers exhibit similar deficits in lipid metabolism, cognitive and behavioral functions, and neurodegeneration. The retina, as part of the CNS, has been studied to investigate the underlying mechanisms of AD, including neuroinflammation, amyloid aggregation, and neurodegeneration. This study explores ApoE's role in AD by analyzing brain and eye samples from Apoe -ko mice, focusing on identifying potential retinal biomarkers associated with ApoE dysfunction. Methods: We compared female Apoe -ko mice on a regular diet to age-matched C57BL/6J controls at 3 and 9 months. Our investigations included microRNAs (miRNAs), their target messenger RNAs (mRNAs), and selected protein markers, including astroglial (Gfap), microglial/macrophage (Iba1 and Trem2) markers, and amyloid precursor protein (APP)/amyloid-β (Aβ) peptides implicated in AD pathogenesis. We also examined female Apoe -ko mice on a high-fat diet versus a regular diet at 9 months for differential miRNA and mRNA expressions. Results: Our findings demonstrated that miRNA levels were generally lower in 3-month-old Apoe -ko mice but increased in 9-month-old mice across five distinct brain regions, as well as in eye tissue and tear fluid. A high-fat diet further enhanced miRNA dysregulation in brain and eye tissues, but not in tear fluid. Target mRNAs were generally higher in the neocortex-hippocampus and eye tissue of 3-month-old Apoe -ko mice but decreased with age, except for glial cell mRNAs like Gfap and Aif1. Protein analysis revealed elevated Gfap expression, and increased APP/Aβ peptide accumulation in the neocortex-hippocampus, including brain endothelial cells at the meninges, as well as in the retina of 9-month-old Apoe -ko mice. These findings highlight ApoE's pivotal role in AD, demonstrating its impact on inflammatory and amyloidogenic/angiogenic miRNA expression, glial homeostasis, and APP/Aβ peptide clearance. The observed upregulation of proinflammatory miR-146a and anti-amyloidogenic/angiogenic miR-15a in 9-month-old Apoe -ko mice suggests their potential as tear-based biomarkers for ApoE dysfunction. [ABSTRACT FROM AUTHOR]

Background: Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity. Methods: Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes. Results: DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis. Conclusions: Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway. [ABSTRACT FROM AUTHOR]

Despite its notoriously mild phenotype, the dystrophin-deficient mdx mouse is the most common model of Duchenne muscular dystrophy (DMD). By mimicking a human DMD-associated metabolic comorbidity, hyperlipidemia, in mdx mice by inactivating the apolipoprotein E gene (mdx-ApoE) we previously reported severe myofiber damage exacerbation via histology with large fibro-fatty infiltrates and phenotype humanization with ambulation dysfunction when fed a cholesterol- and triglyceride-rich Western diet (mdx-ApoEW). Herein, we performed comparative lipidomic and metabolomic analyses of muscle, liver and serum samples from mdx and mdx-ApoEW mice using solution and high-resolution-magic angle spinning (HR-MAS) 1H-NMR spectroscopy. Compared to mdx and regular chow-fed mdx-ApoE mice, we observed an order of magnitude increase in lipid deposition in gastrocnemius muscle of mdx-ApoEW mice including 11-fold elevations in -CH3 and -CH2 lipids, along with pronounced elevations in serum cholesterol, fatty acid, triglyceride and phospholipids. Hepatic lipids were also elevated but did not correlate with the extent of muscle lipid infiltration or differences in serum lipids. This study provides the first lipometabolomic signature of severe mdx lesions exacerbated by high circulating lipids and lends credence to claims that the liver, the main regulator of whole-body lipoprotein metabolism, may play only a minor role in this process. [ABSTRACT FROM AUTHOR]

Background: Accumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer's disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults. Methods: This cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis. Results: A higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P =.010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β =.195; P =.020) and a lower subiculum volume (β = -.206; P =.020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P =.441), glucose metabolism pattern (β = -.099; P =.372), brain perfusion pattern (β = -.106; P =.694) or hippocampus volume (β = -.106; P =.194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison. Conclusions: Although an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life. [ABSTRACT FROM AUTHOR]

Insufficient mechanical loading impairs fracture healing; however, the underlying mechanisms remain unclear. Increasing evidence indicates that Piezo1 plays an important role in fracture healing, although the effect of Piezo1 on the endochondral ossification of chondrocytes has been overlooked. This study reports that mechanical unloading down‐regulates the expression of Piezo1 in chondrocytes and leads to fracture nonunion. Single‐cell sequencing of calluses revealed that specific deletion of Piezo1 in chondrocytes upregulated the expression of apolipoprotein E (ApoE) in hypertrophic chondrocytes, resulting in delayed cartilage‐to‐bone transition due to enhanced chondrocyte senescence. Based on these results, an injectable and thermosensitive hydrogel is developed, which released an ApoE antagonist in situ at the fracture site. This hydrogel effectively attenuated chondrocyte senescence and, thus, promoted cartilage‐to‐bone transition as well as the fracture healing process. Overall, this data provide a new perspective on the activity of chondrocytes in fracture healing and a new direction for the treatment of fracture nonunion caused by insufficient mechanical loading. [ABSTRACT FROM AUTHOR]

Introduction: The effects of viral infections might be apolipoprotein E (apoE) isoform-dependent. In humans, there are three major apoE isoforms, E2, E3, and E4. E4 is associated with the enhanced entry of several viruses into the brain and their disease progression. A concern of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the development of post-acute COVID-19 syndrome, also known as long COVID. Genetic risk factors for developing long COVID were reported. Methods: In this study, we used virus-like particles (VLPs) that include expression of the SARS-CoV-2 nucleocapsid (N), membrane (M), and envelope (E) structural proteins together with S. In the current study, we used human E2, E3, and E4 targeted replacement mice to assess whether these VLPs affect body weight, behavioral and cognitive performance, and circadian body temperatures. Using VLPs allow working outside an ABSL-3 facility. Results: The effects of VLPs on some behavioral measures were apoE isoform-dependent, with the E2 mice being more affected than E3 or E4 mice. The overall decreased activity in the open field containing objects in week 2 indicate that VLPs can also reduce activity levels in an apoE isoform-independent fashion. Discussion: The results of the current study indicate that even in the absence of viral replication, detrimental effects of VLPs on behavioral measures and circadian body temperatures are seen. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the clinical characteristics of thyroid-associated ophthalmopathy (TAO) with hyperlipidemia and to identify the key lipid indicator. Methods: Patients with TAO were recruited to this study and divided into two groups based on the presence of hyperlipidemia. TAO patients with hyperlipidemia were further classified based on the type of hyperlipidemia. Basic and clinical information of the patients were collected, and comparisons between groups were carried out. Correlation analyses, regression analyses, and stratified analysis were performed to assess the correlations and relationship of the serum lipids with the ophthalmic indicators. Results: A total of 273 patients with TAO were recruited, including 158 patients with hyperlipidemia and 115 patients without hyperlipidemia. Patients with hyperlipidemia, especially those with mixed hyperlipidemia, exhibited high intraocular pressure (IOP). Spearman's correlation analysis and partial correlation analysis showed that apolipoprotein E (ApoE) was positively related to IOP levels after controlling for confounding factors, including age, gender, BMI, smoking history, triiodothyronine (T3), and thyrotropin (thyroid-stimulating hormone, TSH). Moreover, multiple linear regression obtained a regression equation including ApoE, gender, age, and BMI and showed that elevated ApoE levels were associated with elevated IOP [ β = 0.072, 95% confidence interval (CI) = 0.037–0.155, p = 0.030]. Stratified analysis highlighted the impact of ApoE on IOP in younger patients (≤48 years), female patients, patients with normal BMI (<24 kg/m2), and patients with a shorter course of ophthalmopathy (≤6 months). Conclusion: Overall, higher IOP levels were observed in patients with hyperlipidemia, especially those with mixed hyperlipidemia. Notably, a higher ApoE was identified as an independent risk factor for higher IOP. This finding confirmed the close relationship between TAO and lipid metabolism and provides a new insight into the pathogenesis research and the long-term management of TAO. [ABSTRACT FROM AUTHOR]

Background Case Presentation Conclusion Lecanemab (Leqembi®) is an anti‐amyloid monoclonal antibody used for the treatment of Alzheimer's disease (AD). However, side effects may occur with lecanemab, including amyloid‐related imaging abnormalities (ARIA), especially in patients with apolipoprotein E ε4 (APOE4) homozygous.A 69‐year‐old woman had a 2‐year history of worsening memory symptoms and was diagnosed with mild cognitive impairment due to AD. Because she carries two copies of the E4 allele of APOE, her doctor did not recommend lecanemab treatment. However, she strongly desired lecanemab treatment and received four infusions of lecanemab. She had no symptoms or neurological abnormalities, but a head MRI before the fifth infusion showed moderate radiographic ARIA; therefore, she was admitted and treated with steroids. One month later, a head MRI showed the ARIA had disappeared.The indications of lecanemab treatment for patients with APOE4 homozygous must be carefully considered due to the higher risk of ARIA. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Many neurodegenerative disorders share a common pathologic feature involving the deposition of abnormal tau protein in the brain (tauopathies). This suggests that there may be some shared pathophysiologic mechanism(s). The largest risk factor for the majority of these disorders is aging, suggesting involvement of the aging process in the shared pathophysiology. We test the hypothesis that an increase in bone morphogenetic protein (BMP) signaling that occurs during aging contributes to the onset and progression of tauopathies.Human induced pluripotent stem cell (iPSC)‐derived neurons from patients with Alzheimer's disease (AD) were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Wildtype mice were used to examine effects of BMP signaling in vivo. P301S (PS19) mice were examined for the effects of BMP signaling in a model of tauopathy.Here, we show that BMP signaling, mediated by non‐canonical p38 signaling, increases tau phosphorylation and release of p‐tau in human iPSC‐derived AD neurons. Further, there is an interaction between BMP signaling and apolipoprotein E4 (ApoE4) that significantly increases tau phosphorylation and release compared with ApoE3 neurons. Inhibiting BMP signaling reduces the changes in tau in the cultured human neurons, and it limits tau pathology and prevents cognitive decline in PS19 mice.Our study suggests that the age‐related increase in BMP signaling may participate in the onset and progression of tau pathology. Thus, therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent development of diseases involving tau hyperphosphorylation. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Cerebral blood flow at rest declines with age. However, age-related changes in functional measures of cerebrovascular health including cerebrovascular reactivity and neurovascular coupling are not well understood. Additionally, the effect of apolipoprotein E (APOE) ε4, a strong genetic risk factor for Alzheimer's disease, on cerebral blood flow and cerebrovascular function remains unclear. APOEε4 positive (APOEε4+; n = 37, age = 63±4y) and APOEε4 negative (APOEε4-; n = 50, age = 63±4y) cognitively unimpaired adults participated in this study. Macrovascular cerebral blood flow and microvascular cerebral perfusion were measured using 4D flow MRI and pseudo-continuous arterial spin labeling MRI, respectively. Cerebrovascular reactivity and neurovascular coupling were assessed by measuring middle cerebral artery blood velocity in response to hypercapnia and the n-back test, respectively. Neurovascular coupling was lower in APOEε4+ compared with APOEε4- adults (P<0.05), despite higher cerebral blood flow and cerebrovascular reactivity to hypercapnia. Alterations in neurovascular coupling may occur early, prior to changes in cognition, in aging APOEε4 carriers. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) prevalence and severity are associated with increased age, female sex, and apolipoprotein E4 (APOE4) genotype. Although estrogen therapy (ET) effectively reduces symptoms of menopause including hot flashes and anxiety, and can reduce dementia risk, it is associated with increased risks of breast and uterine cancer due to estrogen receptor alpha (ERα)-mediated increases in cancer cell proliferation. Because ERβ activation reduces this cell proliferation, selective targeting of ERβ may provide a safer method of improving memory and reducing hot flashes in menopausal women, including those with AD. APOE genotype influences the response to ET, although it is unknown whether effects of ERβ activation vary by genotype. Methods: Here, we tested the ability of long-term oral treatment with a novel highly selective ERβ agonist, EGX358, to enhance object recognition and spatial recognition memory, reduce drug-induced hot flashes, and influence anxiety-like behaviors in female mice expressing 5 familial AD mutations (5xFAD-Tg) and human APOE3 (E3FAD) or APOE3 and APOE4 (E3/4FAD). Mice were ovariectomized at 5 months of age and were then treated orally with vehicle (DMSO) or EGX358 (10 mg/kg/day) via hydrogel for 8 weeks. Spatial and object recognition memory were tested in object placement (OP) and object recognition (OR) tasks, respectively, and anxiety-like behaviors were tested in the open field (OF) and elevated plus maze (EPM). Hot flash-like symptoms (change in tail skin temperature) were measured following injection of the neurokinin receptor agonist senktide (0.5 mg/kg). Results: EGX358 enhanced object recognition memory in E3FAD and E3/4FAD mice but did not affect spatial recognition memory. EGX358 also reduced senktide-induced tail temperature elevations in E3FAD, but not E3/4FAD, females. EGX358 did not influence anxiety-like behaviors or body weight. Discussion: These data indicate that highly selective ERβ agonism can facilitate object recognition memory in both APOE3 homozygotes and APOE3/4 heterozygotes, but only reduce the magnitude of a drug-induced hot flash in APOE3 homozygotes, suggesting that APOE4 genotype may blunt the beneficial effects of ET on hot flashes. Collectively, these data suggest a potentially beneficial effect of selective ERβ agonism for memory and hot flashes in females with AD-like pathology, but that APOE genotype plays an important role in responsiveness. [ABSTRACT FROM AUTHOR]

Objective(s): Alzheimer's disease (AD) is a major public concern and one of the primary types of dementia characterized by memory impairment and cognitive decline. Although the properties of exercise training and cannabidiol (CBD) treatments for improving AD have recently been revealed, the exact mechanisms remain unknown. Therefore, this study highlights the interactive impact of high-intensity interval training (HIIT) and CBD administration on improving cognitive impairment in a rat model of amyloid beta (Aβ)-induced AD through modulating the expression of apolipoprotein E (APOE), presenilin-1, and glutamate proteins. Materials and Methods: After acclimatization, the animals were randomly assigned into seven subgroups: control (CNT), Sham, Alzheimer (AL), Alzheimer + HIIT (AL + HIIT), Alzheimer + cannabidiol (AL + CBD), Alzheimer + CBD + HIIT (AL + CBD + HIIT), and model (sacrificed ten days after surgery to confirm the induction of AD) groups. To induce AD, rats received an intrahippocampal injection of Aβ. The animals in exercise groups performed the HIIT protocol, and the rats in CBD groups were administered 20 mg/kg CBD suspended in sesame oil for six weeks. Following the experimental protocol, serum and hippocampus tissue were collected for histopathological and western blot analysis. Results: Our findings indicated that both HIIT and CBD treatments were efficacious in ameliorating Aβ deposition and modulating biomarkers of AD, including APOE, presenilin-1, and glutamate. However, the interactive effect of HIIT and CBD supplementation was more effective. Conclusion: Our findings demonstrated the positive therapeutic effect of HIIT and CBD interventions, particularly HIIT combined with CBD, on alleviating AD. [ABSTRACT FROM AUTHOR]

Background and purpose: Amyloid β (Aβ), a major biomarker of Alzheimer's disease, leads to tau accumulation, neurodegeneration and cognitive decline. Modelling the trajectory of Aβ accumulation in cognitively unimpaired (CU) individuals is crucial, as treatments targeting Aβ are anticipated. The evolution of Aβ levels was investigated to determine whether it could lead to classification into different groups by studying longitudinal Aβ changes in older CU individuals, and differences between the groups were compared. Methods: A total of 297 CU participants were included from the Alzheimer's Disease Neuroimaging Initiative database, and these participants underwent apolipoprotein E (APOE) genotyping, neuropsychological testing, brain magnetic resonance imaging, and an average of 3.03 follow‐up 18F‐florbetapir positron emission tomography scans. Distinct Aβ trajectory patterns were classified using latent class growth analysis, and longitudinal cognitive performances across these patterns were assessed with a linear mixed effects model. Results: The optimal model consisted of three classes, with a high entropy value of 0.947. The classes were designated as follows: class 1, non‐accumulation group (n = 197); class 2, late accumulation group (n = 70); and class 3, early accumulation group (n = 30). The late accumulation and early accumulation groups had more APOE ε4 carriers than the non‐accumulation group. The longitudinal analysis of cognitive performance revealed that the early accumulation group showed the steepest decline (modified Preclinical Alzheimer's Cognitive Composite with digit symbol substitution [mPACCdigit], p < 0.001; modified Preclinical Alzheimer's Cognitive Composite with trails B [mPACCtrailsB], p < 0.001) and the late accumulation group showed a steeper decline (mPACCdigit, p = 0.014; mPACCtrailsB, p = 0.007) compared to the non‐accumulation group. Conclusions: Our study showed the heterogeneity of Aβ accumulation trajectories in CU older individuals. The prognoses for cognitive decline differ according to the Aβ trajectory patterns. [ABSTRACT FROM AUTHOR]

One of the hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) within the extracellular spaces of the brain as plaques and along the blood vessels in the brain, a condition also known as cerebral amyloid angiopathy (CAA). Clusterin (CLU), or apolipoprotein J (APOJ), is a multifunctional glycoprotein that has a role in many physiological and neurological conditions, including AD. The apolipoprotein E (APOE) is a significant genetic factor in AD, and while the primary physiological role of APOE in the brain and peripheral tissues is to regulate lipid transport, it also participates in various other biological processes, having three basic human forms: APOE2, APOE3, and APOE4. Notably, the APOE4 allele substantially increases the risk of developing late-onset AD. The main purpose of this review is to examine the roles of CLU and APOE in AD pathogenesis in order to acquire a better understanding of AD pathogenesis from which to develop targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to evaluate the potential effects of white tea (WT) in the atherosclerosis process characterized by oxidative stress, inflammation, and dyslipidemia. Methods: In our study, apolipoprotein E knockout (ApoE−/−) mice (RRID: IMSR_JAX:002052) and C57BL/6J mice (RRID: IMSR_JAX:000664) were used. In the atherosclerosis model induced by an atherogenic diet (AD), WT was administered via oral gavage at two different concentrations. The animals were sacrificed by decapitation under anesthesia, and their serum and aortic tissues were collected. Total cholesterol (TC), triglyceride (TG), interleukin (IL)-1β, IL-6, IL-10, IL-12, tumor necrosis factor-α (TNF-α), interferon-γ, myeloperoxidase, paraoxonase-1, lipoprotein-associated phospholipase A2, oxidized low-density lipoprotein (Ox-LDL), lectin-like oxidized LDL receptor (LOX-1), a disintegrin, and metalloprotease (ADAM) 10 and 17 activities were determined via colorimetric, enzyme-linked immunoassay, and fluorometric methods. Results: WT supplementation decreased serum Ox-LDL, LOX-1, TC, and TG levels by approximately 50%. TNF- and IL-6 levels were reduced by approximately 30% in the aortic arch. In addition, ADAM10/17 enzyme activities were found to be reduced by approximately 25%. However, no change in the AD-induced fibrotic cap structure was observed in the aortic root. Conclusions: The findings indicate that white tea effectively reduced oxidative stress, inflammation, and dyslipidemia in atherosclerosis but does not affect atheroma plaque morphology. [ABSTRACT FROM AUTHOR]

Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

We aimed to develop and validate a protein risk score for predicting Alzheimer's disease (AD) and compare its performance with a validated clinical risk model (Cognitive Health and Dementia Risk Index for AD [CogDrisk‐AD]) and apolipoprotein E (APOE) genotypes. The development cohort, consisting of 35,547 participants from England in the UK Biobank, was randomly divided into a 7:3 training–testing ratio. The validation cohort included 4667 participants from Scotland and Wales in the UK Biobank. In the training set, an AD protein risk score was constructed using 31 proteins out of 2911 proteins. In the testing set, the AD protein risk score had a C‐index of 0.867 (95% CI, 0.828, 0.906) for AD prediction, followed by CogDrisk‐AD risk factors (C‐index, 0.856; 95% CI, 0.823, 0.889), and APOE genotypes (C‐index, 0.705; 95% CI, 0.660, 0.750). Adding the AD protein risk score to CogDrisk‐AD risk factors (C‐index increase, 0.050; 95% CI, 0.008, 0.093) significantly improved the predictive performance for AD. However, adding CogDrisk‐AD risk factors (C‐index increase, 0.040; 95% CI, −0.007, 0.086) or APOE genotypes (C‐index increase, 0.000; 95% CI, −0.054, 0.055) to the AD protein risk score did not significantly improve the predictive performance for AD. The top 10 proteins with the highest coefficients in the AD protein risk score contributed most of the predictive power for AD risk. These results were verified in the external validation cohort. EGFR, GFAP, and CHGA were identified as key proteins within the protein network. Our result suggests that the AD protein risk score demonstrated a good predictive performance for AD risk. [ABSTRACT FROM AUTHOR]

Alport syndrome (AS) is one of the most common inherited kidney disorders, involving pathogenic variants of COL4A3, COL4A4 and COL4A5 genes that lead to disruption of the normal structure of collagen IV protein through improper chain or heterotrimer folding or degradation of heterotrimer components. Lipoprotein glomerulopathy (LPG) is an autosomal dominant disease involving APOE gene mutations disturbing lipoprotein metabolism. We report the first case with both AS and LPG in an 11‐year‐old girl. The patient presented with blepharedema, and decreased vision. Laboratory examinations showed hematemesis, proteinuria, hypoproteinemia, hyperlipidemia and progressive renal failure. Renal biopsy showed the changes of LPG and AS. Whole‐exome sequencing (WES) identified two pathogenic variants, c.127C > T in exon 3 of APOE gene, and c.930 + 1G > A in exon 15 of COL4A4 gene. We emphasize the importance of early completion of renal biopsy and WES for early diagnosis of LPG and AS. [ABSTRACT FROM AUTHOR]

Lipoprotein glomerulopathy (LPG) is a rare disorder characterized by the development of glomerular lipoprotein thrombosis. LPG exhibits familial aggregation, with mutations in the apolipoprotein E (APOE) gene identified as the leading cause of this disease. This study aimed to investigate APOE gene mutations and the clinicopathological features in eleven LPG patients. Clinicopathological and follow-up data were obtained by extracting DNA, followed by APOE coding region sequencing analysis. This study analyzed clinical and pathological manifestations, gene mutations, treatment and prognosis. The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients. In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples. APOE gene testing revealed that one patient had no mutations, while the remaining ten patients exhibited mutations in the APOE gene, with three patients presenting with multiple mutations simultaneously. Following the confirmation of LPG diagnosis, treatment with angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) was initiated, and the disease progressed slowly. LPG is histologically characterized by lamellated lipoprotein thrombi in glomeruli, and kidney biopsy is essential for diagnosis. Mutations in the APOE gene are the leading cause of LPG. This study revealed clinicopathological characteristics and APOE gene mutations in patients with LPG, which helps us better understand the disease. [ABSTRACT FROM AUTHOR]

Physical activity is a promising preventative strategy for Alzheimer's disease: it is associated with lower dementia risk, better cognition, greater brain volume and lower brain beta-amyloid. Blood-based biomarkers have emerged as a low-cost, non-invasive strategy for detecting preclinical Alzheimer's disease, however, there is limited literature examining the effect of exercise (a structured form of physical activity) on blood-based biomarkers. The current study investigated the influence of a 6-month exercise intervention on levels of plasma beta-amyloid (Aβ42, Aβ40, Aβ42/40), phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) chain in cognitively unimpaired older adults, and as a secondary aim, whether blood-based biomarkers related to cognition. Ninety-nine community-dwelling older adults (69.1 ± 5.2) were allocated to an inactive control, or to moderate or high intensity exercise groups where they cycled twice weekly for six months. At baseline and six months (post-intervention), fasted blood was collected and analysed using single molecule array (SIMOA) assays, and cognition was assessed. Results demonstrated no change in levels of any plasma biomarker from pre- to post-intervention. At baseline, higher NfL was associated with poorer cognition (β = -0.33, SE = 0.13, adjusted p =.042). Exploratory analyses indicated higher cardiorespiratory fitness was associated with higher NfL and GFAP levels in apolipoprotein E (APOE) ε4 non-carriers compared to ε4 carriers (NfL, β = -0.43, SE = 0.19, p =.029; GFAP, β = -0.41, SE = 0.20, p =.044), though this association was mediated by body mass index (BMI). These results highlight the importance of considering BMI in analysis of blood-based biomarkers, especially when investigating differences between APOE ε4 carriers and non-carriers. Our results also indicate that longer follow-up periods may be required to observe exercise-induced change in blood-based biomarkers. [ABSTRACT FROM AUTHOR]

Background: Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain. Aims: By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia. Method: Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively. Results: Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5–15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status. Conclusions: This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention. [ABSTRACT FROM AUTHOR]

Background and Objectives: Alzheimer's dementia is a progressive neurodegenerative disease that affects memory abilities due to genetic and environmental factors. A well-known gene that influences the risk of Alzheimer's disease is the apolipoprotein E (APOE) gene. The APOE gene is involved in the production of a protein that helps transport cholesterol and other types of fat in the bloodstream. Problems in this process are thought to contribute to the development of Alzheimer's disease. APOE comes in several forms, which are called alleles (ε2, ε3, ε4). Materials and Methods: Therefore, our study aims to identify those subjects with a higher genetic risk through the polymorphism of the APOE gene, using a population screening in patients with a clinical diagnosis of AD in a region of Spain, Castilla y León, as potential biomarkers and to identify individuals at increased genetic risk by polymorphism of the APOE gene. An observational case-control study was conducted in Castilla y León (Spain). Saliva samples were collected and the ApoE gene was analyzed by PCR and agarose gel electrophoresis, respecting ethical criteria. Results: In the Alzheimer's population in Castilla y León, a high prevalence of ApoE3 (74%) was found, followed by ApoE4 (22%); in addition, a higher presence of the ε4 allele was found in the Alzheimer's disease (AD) group than in the control group. It was also observed that the ε2/ε2 genotype was not found in any individual with AD but was found in healthy subjects and that the opposite was observed for the ε4/ε4 genotype. The odds ratio (OR) indicated a risk four times greater of having AD if having the ε4 allele. Conclusions: The demonstrated relation between the different isoforms and the likelihood of developing AD has led to its consideration as a biomarker and a potential pre-symptomatic therapy. The molecular mechanisms that confer a disruptive and protective role to ApoE4 and ApoE2, respectively, are still being studied. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a degenerative disorder of the central nervous system that predominantly affects the elderly.The Apolipoprotein E (ApoE) gene is identified as the most significant genetic factor associated with AD.This article reviews current findings on the relationship between ApoE and AD, the impact of APOE gene polymorphisms on AD, the interaction between ApoE and other pathogenic factors, and the role of ApoE in AD.Additionally, it discusses the diagnosis and treatment of AD to enhance the understanding of its pathogenesis and to provide new perspectives for the prevention and management of the disease.

Background: Apolipoprotein Ɛ4 has been established as a risk factor for cognitive impairment and dementia among Caucasians; however, the relationship among Black Africans has not been consistent. Aims: This study aimed to determine the sex-related differences in mild cognitive impairment (MCI) and its association with apolipoprotein E (APOE) polymorphism and sociodemographic factors amongst community-dwelling older persons in Kano, Nigeria. Materials and Methods: One hundred and forty-three participants (males = 65 and females = 78) were randomly recruited. APOE was genotyped from peripherally extracted genomic DNA using the sequence-specific primer polymerase chain reaction with Hhal digestion. Cognition was assessed using the Montreal Cognitive Assessment Basic (MoCA-B). Data were analysed using the SPSS software. Results: The mean age of the participants was 65.69 years. The prevalence of MCI was 63.64%, and females were more affected (73.08% vs. 52.31%, χ2 = 6.609; P = 0.010). The frequency of APOE genotypes was: E3/3-48%, E3/4-25.9%, E2/3-15.4%, E2/4 and E4/4-4.2%, and E2/2-2.8%, while its allelic distribution was: Ɛ3-68.2%, Ɛ4-19.2%, and Ɛ2-12.6%. Age and years of formal education were the independent predictors of the MoCA-B score. They explained 68% of the variance in MoCA-B score, while possession of at least one Ɛ4 allele (χ2 = 37.949, P < 0.001), low level of formal education (χ2 = 20.035, P = 0.001), being female (χ2 = 6.609, P = 0.010), being single (χ2 = 6.303, P = 0.012), and having a lower monthly income (χ2 = 16.884, P = 0.001) were associated with MCI. Conclusions: The prevalence of MCI among older persons in Kano, Nigeria, is high and is associated with low levels of education, female sex, advanced age, low income, and APOE Ɛ4.

PURPOSE: To determine whether microstructural retinal changes, tumor features, and apolipoprotein E (APOE) ε4 polymorphism are correlated with clinically detectable treatment-associated cognitive dysfunction (TACD) in patients with lower-grade gliomas. DESIGN: Cohort study. PARTICIPANTS AND CONTROLS: Sixteen patients with lower-grade glioma at a United States academic ophthalmology department between January 2021 and November 2023. Normal controls were recruited from convenient sampling. METHODS: Montreal Cognitive Assessment (MoCA) scores and retinal changes were assessed in 6-month intervals. Apolipoprotein E genotyping was performed, and tumor details were recorded. Partial least-squares discriminant (PLSD) model was established to evaluate the association between TACD with APOE genotype, ophthalmic, and tumor features. MAIN OUTCOME MEASURES: The main outcome measure was cognitive status as measured by the MoCA score and analyzed in relation to ophthalmic measurements, tumor features, and APOE genotype. RESULTS: Median time to first eye examination was 34 months (2-266) from tumor diagnosis and 23 months (0-246) from radiation. Nine patients (56%) had abnormal cognition (MoCA

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimers Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimers disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.