APOE Gene Research Articles

Untangling the Genetic Threads of Alzheimer's: Insights into Risk Factors and Biomarkers.

Dementia is a comprehensive term that refers to illnesses characterized by a decline in cognitive memory and other cognitive functions, affecting a person's overall ability to operate. The exact causes of dementia are unknown to this day. The heterogeneity of Alzheimer's indicates the contribution of genetic polymorphism to this disease. This disease is the most prevalent and damaging illness. Studies indicate that the global prevalence of Alzheimer's disease (AD) exceeds 26 million individuals. Investigation of variations in many genes indicates that these variations may be linked to the susceptibility to AD. Additional genetic factors could potentially influence AD. Analysis of several single-nucleotide polymorphisms in this context reveals a correlation between certain variants and AD. Regardless, Alzheimer's disease is always influenced by a particular APOE gene allele. The study's findings indicate that risk of Alzheimer's disease (AD) is linked to polymorphisms in the following genes: BDNF, presenilin-1 (PS-1), presenilin-2 (PS-2), LRP, APP, CTSD,5-6HT, TREM2, TNF-α, LPL, Clusterin (CLU), SORL1 (Sortilin-Related Receptor), PICALM, Complement Receptor 1 (CR1), and APOE genes.

Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features.

Apolipoprotein E (apoE) is a key apoprotein in lipid transport and is susceptible to genetic mutations. ApoE variants have been studied for four decades and more than a hundred of them have been reported. This paper presents an up-to-date review of the function and structure of apoE in lipid metabolism, the E2, E3, and E4 isoforms, the APOE gene, and various pathologies, such as familial type III hyperlipidemia and lipoprotein glomerulopathy, caused by apoE variants. Alzheimer's disease was barely mentioned in this paper. But this review should help researchers obtain a comprehensive overview of human apoE in lipid metabolism.

Identifying genetic susceptibility loci associated with human coronary artery disease.

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.

Hyperlipoproteinemia(a): the role of antisense­­oligonucleotides in reduction of lipoprotein(a) level. Literature review

The literature review is devoted to a relevant problem of correction of elevated level of lipoprotein(a) (LP(a)) which is a risk factor (RF) for atherosclerotic cardiovascular diseases (ACVD) and demonstrates a stability to action of existing lipid‑lowering drugs (LLD) due to genetic determination of apolipoprotein(a) (apo(a)), a structural component of LP(a) molecule. Since human lipid metabolism is regulated by many genes, the majority of them, in particular, apo(a) gene can be potential targets for innovative antisense therapy, a method of treatment based on reduction of synthesis of LP(a) involved in the development of ACVD through inhibition of apo(a) matrix ribonucleic acid (mRNA) translation due to connection with complementary short sequences called antisense oligonucleotides (ASO). Update insights into the structure and pathophysiological role of LP(a) in atherothrombosis, a necessity of hyperlipoproteinemia(a) correction caused by its proatherosclerotic and prothrombotic effects are given. A focus was made on innovative LLD with high potential in treatment of ACVD and correction of their risk factors, particularly on ASO capable of blocking a translation of apo(a) mRNA. Principal mechanisms of ASO action, the ways of their delivery to mRNA targets are presented. The data of studies on LP(a) reduction with mipomersen, pelacarsen, SLN360 agent, olpasiran and lepodisiran are presented. It is emphasized that despite the efficacy of enumerated ASO in LP(a) reduction, there are unknown long­­term consequences of its intensive reduction, particularly an influence on cardiovascular events and the functional state of organs and their systems in different diseases. The only ASO drug approved by the US Food and Drug Administration is mipomersen recommended for correction of low­­density lipoprotein cholesterol and LP(a) levels due to its ability to block apolipoprotein B­­100 synthesis. In Europe mipomersen was not registered because of its unfavorable safety profile. Thus, despite the prospects for developing new drugs based on antisense technologies, many questions remain about their efficacy and safety, especially for LLD intended for long­­term use.

MANIFESTAÇÕES E COMORBIDADES DA DOENÇA DE ALZHEIMER: UMA REVISÃO SISTEMÁTICA

Objective: The aim of this review was to report the current knowledge on the main clinical manifestations and comorbidities associated with Alzheimer's disease (AD). Methodology: Searches were performed in the PubMed Central (PMC) databases. Three descriptors were used in combination with the Boolean term "AND": Alzheimer Disease, Signs and Symptoms, Clinical Diagnosis. From this search, 440 articles were found, which were subsequently submitted to the selection criteria. After applying the inclusion and exclusion criteria, 25 articles were selected from the PubMed database to compose the review. Results: The studies highlight the diversity of clinical manifestations of AD, which include memory loss, cognitive difficulties, language problems, and mood swings. Comorbidities often seen in AD patients include cardiovascular disease, diabetes mellitus, depression, and migraine. The identification of genetic factors and biomarkers, such as alterations in the ApoE, ENPP6 and SOMA1 genes, reveals the biological complexity of the disease. Sex differences in AD manifestations are significant, with women having a higher prevalence of depressive and psychotic symptoms, while men are more prone to apathy. Innovative therapeutic approaches, such as modulation of brain rhythms and artificial rhythmic stimulation, show promise for improving cognitive function. Conclusion: The integration of multidisciplinary and innovative approaches is essential for advancing the diagnosis and treatment of AD. A detailed understanding of clinical manifestations and comorbidities, combined with the identification of biomarkers, is essential to develop more effective therapies. In short, progress in AD management requires a holistic and collaborative approach, aimed at meeting the individual needs of patients and promoting their overall well-being.

The role of APOE gene polymorphisms in lung adenocarcinoma susceptibility and lipid profile

BackgroundAPOE gene polym orphisms have been linked to Alzheimer’s disease and coronary heart diseases. However, their relationship with lung adenocarcinoma (LUAD) remains uncertain.MethodsThis 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.ResultsThe APOE ϵ2 allele had been significantly more frequently occurring in the LUAD group than in the control group (15.5% vs. 7%, P &amp;lt;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.ConclusionIndividuals 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.

Aging and head and neck cancer insights from single cell and spatial transcriptomic analyses

BackgroundHead and neck squamous cell carcinoma(HNSCC) is the sixth most common malignancy worldwide, with more than 890,000 new cases and 450,000 deaths annually. Its major risk factors include smoking, alcohol abuse, aging, and poor oral hygiene. Due to the lack of early and effective detection and screening methods, many patients are diagnosed at advanced stages with a five-year survival rate of less than 50%. In this study, we deeply explored the expression of Aging-related genes(ARGs) in HNSCC and analyzed their prognostic significance using single-cell sequencing and spatial transcriptomics analysis. This research aims to provide new theoretical support and directions for personalized treatment.Annually, more than 890,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally, leading to 450,000 deaths, making it the sixth most common malignancy worldwide. The primary risk factors for HNSCC include smoking, alcohol abuse, aging, and poor oral hygiene. Many patients are diagnosed at advanced stages due to the absence of early and effective detection and screening methods, resulting in a five-year survival rate of less than 50%. In this research, single cell sequencing and spatial transcriptome analysis were used to investigate the expression of Aging-related genes (ARGs) in HNSCC and to analyse their prognostic significance. This research aims to provide new theoretical support and directions for personalized treatment.MethodsIn this study, we investigated the association between HNSCC and AGRs by utilizing the GSE139324 series in the GEO database alongside the TCGA database, combined with single-cell sequencing and spatial transcriptomics analysis. The data were analyzed using Seurat and tSNE tools to reveal intercellular communication networks. For the spatial transcriptome data, SCTransform and RunPCA were applied to examine the metabolic activities of the cells. Gene expression differences were determined through spacerxr and RCTD tools, while the limma package was employed to identify differentially expressed genes and to predict recurrence rates using Cox regression analysis and column line plots. These findings underscore the potential importance of molecular classification, prognostic assessment, and personalized treatment of HNSCC.ResultsThis study utilized HNSCC single-cell sequencing data to highlight the significance of ARGs in the onset and prognosis of HNSCC. It revealed that the proportion of monocytes and macrophages increased, while the proportion of B cells decreased. Notably, high expression of the APOE gene in monocytes was closely associated with patient prognosis. Additionally, a Cox regression model was developed based on GSTP1 and age to provide personalized prediction tools for clinical use in predicting patient survival.ConclusionsWe utilized single-cell sequencing and spatial transcriptomics to explore the cellular characteristics of HNSCC and its interaction with the tumor microenvironment. Our findings reveal that HNSCC tissues show increased mononuclear cells and demonstrate enhanced activity in ARGs, thereby advancing our understanding of HNSCC development mechanisms.

Apolipoprotein (APOA1, APOE, CLU) genes expression in the CA3 region of the hippocampus in an ischemic model of Alzheimer's disease with survival up to 2 years.

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. 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. 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. 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. 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.

Quantitative and Kinetic Proteomics Reveal ApoE Isoform-dependent Proteostasis Adaptations in Mouse Brain.

Apolipoprotein E (ApoE) polymorphisms modify the risk of Alzheimer's disease with ApoE4 strongly increasing and ApoE2 modestly decreasing risk relative to the control ApoE3. To investigate how ApoE isoforms alter risk, we measured changes in proteome homeostasis in transgenic mice expressing a human ApoE gene (isoform 2, 3, or 4). The regulation of each protein's homeostasis is observed by measuring turnover rate and abundance for that protein. We identified 4849 proteins and tested for ApoE isoform-dependent changes in the homeostatic regulation of ~2700 ontologies. In the brain, we found that ApoE4 and ApoE2 both lead to modified regulation of mitochondrial membrane proteins relative to the wild-type control ApoE3. In ApoE4 mice, lack of cohesion between mitochondrial membrane and matrix proteins suggests that dysregulation of proteasome and autophagy is reducing protein quality. In ApoE2, proteins of the mitochondrial matrix and the membrane, including oxidative phosphorylation complexes, had a similar increase in degradation which suggests coordinated replacement of the entire organelle. In the liver we did not observe these changes suggesting that the ApoE-effect on proteostasis is amplified in the brain relative to other tissues. Our findings underscore the utility of combining protein abundance and turnover rates to decipher proteome regulatory mechanisms and their potential role in biology.

Synthesis and Characterization of Transferrin and Cell-Penetrating Peptide-Functionalized Liposomal Nanoparticles to Deliver Plasmid ApoE2 In Vitro and In Vivo in Mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by the aggregation of amyloid-β plaques and neurofibrillary tangles in the brain, leading to synaptic dysfunction and neuronal degeneration. Recently, new treatment approaches involving drugs such as donanemab and lecanemab have been introduced for AD. However, these drug regimens have been associated with adverse effects, leading to the exploration of gene therapy as a potential treatment option. The apolipoprotein E (ApoE) isoforms (ApoE2, ApoE3, and ApoE4) play pivotal roles in AD pathology, with ApoE2 known for its protective effects against AD, making it a promising candidate for gene therapy interventions. However, delivering therapeutics across the blood-brain barrier (BBB) remains a crucial challenge in treating neurological disorders. Liposomes, lipid-based vesicles, are effective nanocarriers due to their ability to shield therapeutics from degradation, though they often lack specificity for brain delivery. To address this issue, liposomes were functionalized with cell-penetrating peptides such as penetratin (Pen), cingulin (Cgn), and a targeting ligand transferrin (Tf). This modification strategy aimed to enhance the delivery of therapeutic ApoE2 plasmids across the BBB to neurons, thereby increasing the level of ApoE2 protein expression. Experimental findings demonstrated that dual-functionalized liposomes (CgnTf and PenTf) exhibited higher cellular uptake, biodistribution, and transfection efficiency than single-functionalized (Pen, Cgn, or Tf) and nonfunctionalized liposomes. In vitro studies using primary neuronal cells, bEnd.3 cells, and primary astrocytes consistently supported these findings. Following a single dose treatment via tail vein administration in C57BL6/J mice, in vivo biodistribution results showed significantly higher biodistribution levels in the brain (∼12% ID/gram of tissue) for dual-functionalized liposomes. Notably, treatment with dual-functionalized liposomes resulted in a 2-fold increase in ApoE2 expression levels compared to baseline levels. These findings highlight the potential of dual-functionalized liposomes as an efficacious delivery system for ApoE2 gene therapy in AD, highlighting a promising strategy to address the disease's underlying mechanisms.

Optimized prime editing of the Alzheimer's disease-associated APOE4 mutation.

Gene editing strategies to safely and robustly modify the Alzheimer's disease-associated APOE4 isoform are still lacking. Prime editing (PE) enables the precise introduction of genetic variants with minimal unintended editing and without donor templates. However, it requires optimization for each target site and has not yet been applied to APOE4 gene editing. Here, we screened PE guide RNA (pegRNA) parameters and PE systems for introducing the APOE4 variant and applied the optimized PE strategy to generate disease-relevant human induced pluripotent stem cell models. We show that introducing a single-nucleotide difference required for APOE4 correction inhibits PE activity. To advance efficient and robust genome engineering of precise genetic variants, we further present a reliable PE enrichment strategy based on diphtheria toxin co-selection. Our work provides an optimized and reproducible genome engineering pipeline to generate APOE4 disease models and outlines novel strategies to accelerate genome editing in cellular disease model generation.

Sex dependent pleiotropic effects of Apolipoprotein (ApoE) 4 on executive function in mice and humans

AbstractBackgroundApoE4 is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD). However, ApoE4 has also been suggested to exhibit antagonistic pleiotropy, a phenomenon by which some allelic variations of a gene promote fitness during certain periods of life but may be detrimental in others. Previous work suggests that ApoE4 carriers exhibit superior performance on executive function tasks in early and middle age, while later in life (&gt;70 years) ApoE4 carriers experience greater cognitive decline across multiple domains. We examined this ApoE4 antagonistic pleiotropy hypothesis using a cross‐species translational approach, focusing on cognitively unimpaired human adult ApoeE4 carriers and non‐carriers who were within a relatively younger age range (&lt;70 years). We complement this using knock‐in mouse models that express humanized wild‐type App, MAPT, and ApoE3 or ApoE4 genes. To quantify executive function in both human and mouse, we used cross‐species touchscreen based Continuous Performance Task (CPT) to assess selective attention.MethodHuman participants were recruited from the PREVENT‐AD program at the Douglas Research Centre. Human touchscreen CPT testing was conducted using an MS SurfacePro. Mice were tested with the same task as humans using an operant chamber platform.ResultOur initial behavioural results suggest that ApoE4 facilitates attentional processes in both older adults and mouse ApoE4 carriers, as indexed by discrimination performance on the CPT. Further strengthening this translational pattern, we found that the facilitative effect of ApoE4 on CPT was more pronounced in female ApoE4 carriers of both species. In mice, we were able to examine this ApoE‐dependent effect on attention longitudinally. Consistent with antagonistic pleiotropy hypothesis, ApoE4 female mice present a higher CPT performance early in life (6‐9 months of age) when compared to ApoE3 mice, but this difference was reduced by 12 months of age.ConclusionTaken together, these results support the ApoE4 antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life in both female humans and mice. These new mouse models, in combination with fully translatable touchscreen tests of cognition, can be used to explore potential mechanisms by which ApoE4 can affect different aspects of brain function across the life span

Impact of regional MAPT, APOE, and Aβ on tau propagation in Alzheimer’s disease: Insights from a connectome‐based simulation model

AbstractBackgroundTau pathology, a hallmark of Alzheimer’s disease (AD), is thought to spread cell‐to‐cell via axonal connections, beginning focally before expanding throughout the brain. This study uses computational models to investigate the interplay between network spread and regional vulnerability in influencing tau spread, focusing specifically on MAPT and APOE genes, and Aβ plaques.Method66 regional (Desikan‐Killiany atlas) tau‐PET standardized uptake value ratio (SUVR) values were extracted from participants in the Swedish BioFINDER‐2 study: 429 cognitively normal (CN), 91 subjective cognitive decline (SCD), 168 mild cognitive impairment (MCI), and 182 AD. Values were adjusted for mean choroid plexus signal and converted to tau‐positive probabilities using two‐component Gaussian mixture models. The Susceptible‐Infectious‐Recovered (SIR) model (Fig. 1A) was employed to simulate tau spread through brain networks measured using structural connectivity from young individuals. We examined the roles of MAPT, APOE, and Aβ in tau propagation by parameterizing them regionally to influence tau synthesis, clearance, spreading, or misfolding. Regional MAPT and APOE were extracted from Allen Brain Atlas, and Aβ from Aβ‐PET. Performance of both baseline models (connectivity‐only) and models incorporating regional biological information were evaluated based on their ability to reconstruct observed regional tau levels. Performance was evaluated across the whole sample and groups based on diagnosis, APOE e4 carriage and Aβ positivity.ResultThe SIR model recapitulates observed tau patterns, suggesting connectivity‐based propagation in early‐stage regions (Fig. 1B, C). Allowing regional MAPT to moderate normal tau synthesis improved the model fit overall, and for all groups except CN or Aβ‐ participants (Fig. 2,3). Regional APOE or Aβ information did not enhance the model performance overall (Fig. 2B, C). However, allowing regional APOE to moderate tau clearance showed better performance in APOE e4 carriers vs. non‐carriers, and allowing regional Aβ to moderate tau spread improved performance compared to baseline model among Aβ+ individuals (Fig. 3).ConclusionOur results suggest that brain connectivity explains early temporal lobe tau spread patterns, while regional intrinsic (MAPT) and disease‐related (Aβ) susceptibility may influence spread of tau into other regions at later stages. Future work will test other hypotheses of tau spread by refining this model with additional biological information.

Stimulation of Locus Ceruleus Inputs to the Prelimbic Cortex in Mice Induces Cell Type-Specific Expression of the Apoe Gene.

The medial frontal cortex (mFC) and locus ceruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision-making. Regulators of these brain regions at the molecular level are not well understood but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC and subsequent bulk RNA sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL or a control virus and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision-making and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease.

Extensive antagonistic genetic underpinnings of sex disparities in Alzheimer’s disease and hypertension

AbstractBackgroundThe Alzheimer’s Association reports that more than two‐thirds of the approximately 5 million Alzheimer’s disease (AD) cases in the USA are women. With studies suggesting a high genetic heritability for AD, gaining a better understanding of the genetic architecture underlying sex disparities in AD and its risk factors could enhance the understanding of their mechanisms.MethodWe conducted genome‐wide association studies (GWAS) and pleiotropic meta‐analysis of AD and its risk factor—hypertension—in men and women of European ancestry. The AD GWAS focused on 168,962 men (including 6,229 cases) and 199,668 women (including 7,628 cases) from 10 cohorts. The hypertension GWAS included 177,597 men (96,835 cases) and 205,482 women (88,861 cases) from eight of the 10 AD cohorts. Sex‐specific associations were characterized by the Wald chi‐square test and Fisher’s method, and their significance was assessed at a false discovery rate q‐value of 5% or less.ResultGWAS of AD and hypertension identified 176 and 195 loci, respectively, on all chromosomes with the differences in the effects between sexes attaining q&lt;0.05. Associations with AD were of the same directions in men and women only in one—the APOE gene—locus, with significantly larger adverse effect for the ε4‐encoding rs429358 polymorphism in women (β = 1.35, CI = 1.30‐1.41) than men (β = 1.16, CI = 1.10‐1.22). Associations with hypertension were of the same directions in each sex in 74 of 195 loci on all chromosomes, except chromosome 14. The ε4 allele showed no association with hypertension in either sex. No significant differences between sexes in the significant protective associations with AD and hypertension were identified for the ε2 allele. Our analyses revealed seven pleiotropic loci mapped to COL24A1, MGC4859‐PHF14, MFHAS1‐ERI1, SBF2, KICS2, BCL11B, and RPAP1 gene clusters characterized by the differences in the associations with AD and hypertension between sexes at q&lt;0.05. In three underlined clusters, the associations with hypertension were of the same direction in men and women.ConclusionAlthough the APOE ε4 allele partly underlies AD‐related sex disparities, the most substantial contribution comes from antagonistic relationships between genes and AD in men and women. Sex‐specific pleiotropic loci suggest contribution of hypertension to these AD‐related sex disparities.

The impact of PPARγ and ApoE gene polymorphisms on susceptibility to diabetic kidney disease in type 2 diabetes mellitus: a meta-analysis

BackgroundGlobally, diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease, imposing substantial social and economic costs. This meta-analysis was designed to provide valuable insights into gene-disease interactions by investigating the potential association between lipid metabolism gene polymorphisms and the risk of DKD.MethodsAn electronic literature search was conducted on MEDLINE Complete, Web of Science, Embase, and PubMed. A total of 18 studies on the peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala variant and 20 publications concerning apolipoprotein E (ApoE) gene polymorphism were included in the meta-analysis.ResultsOverall, the PPARγ Pro12Ala polymorphism was found to be significantly associated with a decreased DKD risk (OR = 0.74, 95% CI: 0.62–0.88). In subgroup analysis, Ala carriers were less susceptible to DKD than Pro homozygotes among Asian (OR = 0.73, 95% CI: 0.56–0.95) and Caucasian populations (OR = 0.74, 95% CI: 0.59–0.93). Subgroup analysis stratified by albuminuria categories showed that the PPARγ Pro12Ala polymorphism reduced the risk of both microalbuminuria and macroalbuminuria with corresponding ORs of 0.58 (95% CI: 0.43–0.78) and 0.68 (95% CI: 0.53–0.86). Sensitivity analysis confirmed the robustness of the meta-analysis results. However, publication bias was identified in the subgroup analysis of the Caucasian population. The primary analysis of the ApoE gene polymorphism yielded significant findings, indicating that ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes increase the risk of DKD (ε2/ε2 vs. ε3/ε3: OR = 1.93, 95% CI: 1.03–3.61; ε2/ε3 vs. ε3/ε3: OR = 1.63, 95% CI: 1.19–2.25; ε2/ε4 vs. ε3/ε3: OR = 1.87, 95% CI: 1.37–2.55). However, sensitivity analysis suggested that influential and Hardy-Weinberg equilibrium (HWE)-violating studies may impact the overall effect estimates.ConclusionsA meta-analysis showed that PPARγ gene polymorphism may be a protective factor for DKD, whereas the ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes are associated with an increased risk of DKD. However, the role of ApoE gene polymorphism in susceptibility to DKD is less certain and requires further evaluation.

A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in mild cognitive impairment and Alzheimer's disease.

Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored. To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD. In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy. An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups. The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.

Analysis of Alzheimer's disease associated deleterious non-synonymous single nucleotide polymorphisms and their impacts on protein structure and function by performing in-silico methods.

Alzheimer's disease (AD) is a neurodegenerative disorder that is presented with a progressive loss of memory, a decline in cognitive abilities and multiple changes in behavior. Its pathogenicity has been linked to genetic factors in approximately 60-80% of the cases specifically APOE gene family and as well as other gene families. This study utilized advanced computational biology methods to analyze AD-associated nsSNPs extracted from the NHGRI-EBI GWAS Catalog. Ensembl Variant Effect Predictor (VEP) is used to annotate the variants associated with AD. Annotated missense variants were subjected to PolyPhen-2, SNPs&Go, PredictSNP servers which were used to predict pathogenicity of selected missense variants by protein sequence information. DynaMut and DUET servers were applied to determine protein stability due to the amino acid change by integrating protein structure information. Missense variations associated with AD were annotated to 26 proteins and further analyzed in our study. Following rigorous data filtration steps, 15 candidate variants (13 proteins) were identified and subjected to sequence and structure-based analysis. Finally in this in-silico study, five deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in ACKR2(V41A), APOE(R176C), ATP8B4(G395S), LAMB2(E987K), and TOMM40(R239W), and these findings were subsequently backed-up by existing in-vivo and in-vitro literature. This study not only provides invaluable insight into the intricate pathogenic mechanisms underlying AD but also offers a distinctive perspective that paves the way for future, more comprehensive investigations aimed at unraveling the molecular intricacies responsible for the development and progression of AD. Nonetheless, it is imperative that further rigorous in vivo and in vitro experiments are conducted to validate and expand upon the findings presented here.

Prevalence of ApoE Alleles in a Spanish Population of Patients with a Clinical Diagnosis of Alzheimer's Disease: An Observational Case-Control Study.

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.

Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia.

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.