Factors Influencing Alzheimer's Disease Risk: Whether and How They are Related to the APOE Genotype / 神经科学通报·英文版

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.

Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis.@*METHODS@#The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5, 0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6, 0.1 mL of 1,000 µg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7, DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8, DMOG and 0.1 mL of 1,000 µg/mL DLT submicron powder solution). Groups 1-4 used mature adipocytes and groups 5-8 used HIF-1 α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment, real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1 α and Angptl4. In animal experiments, the CIH model in ApoE-/- mice was established. Sixteen mice were complete randomly divided into 4 groups including sham group, CIH model group [intermittent hypoxia and normal saline (2 mL/time) gavage once a day]; Angptl4 Ab group [intermittent hypoxia and Angptl4 antibody (30 mg/kg) intraperitoneally injected every week]; DLT group [intermittent hypoxia and DLT (250 mg/kg) once a day], 4 mice in each group. After 4-week treatment, enzyme linked immunosorbent assay was used to detect the expression levels of serum total cholesterol (TC) and triglyceride (TG). Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques.@*RESULTS@#Angptl4 expression was dependent on HIF-1 α, with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1 α -transfected cells. DLT inhibited HIF-1 α and Angptl4 mRNA expression (P<0.05 or P<0.01) and reduced HIF-1 α and Angptl4 protein expressions with DMOG in mature adipocytes (all P<0.01), as the effect on HIF-1 α protein also existed in the presence of siHIF-1 α (P<0.01). ApoE-/- mice treated with CIH had increased TG and TC levels (all P<0.01) and atherosclerotic plaque. Angptl4 antibody and DLT both reduce TG and TC levels (all P<0.01), as well as reducing atherosclerotic plaque areas, narrowing arterial wall thickness and alleviating atherosclerotic lesion symptoms to some extent.@*CONCLUSION@#DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1 α-Angptl4 mRNA signaling pathway.

Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression / 南方医科大学学报

OBJECTIVE@#To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC).@*METHODS@#Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining.@*RESULTS@#ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007).@*CONCLUSION@#BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells.

Correlation of serum lipids levels of Alzheimer's disease patients with sex, age and apolipoprotein E gene polymorphism / 中华预防医学杂志

Objective: To explore the correlation of serum lipids levels of Alzheimer's disease (AD) patients with sex, age and apolipoprotein E (Apo E) gene polymorphism. Methods: The retrospective study method was used, and 407 AD patients (142 males and 265 females, aged 52-91 years) were selected from Beijing Tiantan Hospital from January 2015 to August 2021 as the research target, and 894 healthy persons (339 males and 555 females, aged 52-94 years) who did body examination were selected as the control group. The AD patients were divided into four age groups according to the age interval of 10 years, including 85 aged 50-59 years, 163 aged 60-69 years, 119 aged 70-79 years, and 40 aged more than 80 years. The serum lipids levels were detected by biochemical analyzer, including triglycerides (TG), cholesterol (CHO), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoproteinA1(Apo A1) and apolipoprotein B (Apo B). ApoE gene polymorphism were detected by PCR fluorescent probe method. Mann-Whitney U test and Kruskal-Wallis H test were used to compare the serum lipids levels in each group. Results: The levels of serum CHO and LDL-C were 3.30(1.41,4.82) mmol/L and 1.76(1.39,2.78) mmol/L in AD patients, and 4.84(4.24, 5.56) mmol/L and 2.91(2.36, 3.57) mmol/L in control group, and the levels of serum CHO and LDL-C of AD patients were significantly lower than control group (Z=-15.172,Z=-14.583 , P<0.001, P<0.001). The levels of serum HDL-C and Apo B were 1.84(1.30, 3.88) mmol/L and 1.17(0.85, 1.57) g/L in AD patients, and 1.39(1.18, 1.64) mmol/L and 0.93(0.81, 1.09) g/L in control group, and the levels of serum HDL-C and Apo-B of AD patients were significantly higher than control group (Z=-12.249 , Z=-9.706 , P<0.001, P<0.001). There was no significant difference in TG and Apo A1 between 2 groups (Z=-1.577 , Z=-0.408 , P=0.115, P=0.683). The levels of TG, CHO, LDL-C in female AD patients were significantly higher than male patients (Z=-2.737 , Z=-3.963 , Z=-4.417, P=0.006, P<0.001, P<0.001). There were significant differences in TG, CHO, HDL-C, LDL-C, Apo A1 and Apo B among AD patients of all age groups (Z=11.263 , Z=10.060 , Z=40.246 , Z=10.451 , Z=24.315 , Z=19.922 , P=0.010 , P=0.018 , P<0.001 , P=0.015 , P<0.001 , P<0.001). The serum CHO and LDL-C levels were positively correlated with age (rs=0.160, rs=0.174, P=0.001, P<0.001), and HDL-C, Apo A1 and Apo B levels were negatively correlated with age (rs=-0.312, rs=-0.272, rs=-0.146, P<0.001, P<0.001, P=0.003), and there was no correlation between TG level and age in AD patients (rs=0.086, P=0.082). There were 3 cases (3.33%) of E2, 43 cases of E3 (47.78%) and 44 cases of E4 (48.89%) in AD patients, and 22 cases (12.72%) of E2, 117 cases of E3 (67.63%) and 34 cases of E4 (19.65%) in control group. There was significant difference in Apo E genotype distribution between AD patients and control group (χ²=26.381 , P<0.001). Apo E4 was the most common genotype in AD patients, and the proportion was 48.89%. Except for Apo A1(Z=7.821 , P=0.020), there was no significant difference in TG, CHO, HDL-C, LDL-C and Apo B levels among all patients with different genotypes (Z=3.732 , Z=1.677 , Z=1.455 , Z=1.619 , Z=2.202 , P=0.155, P=0.432, P=0.483, P=0.445, P=0.333). Conclusion: The levels of CHO and LDL-C decreased while the levels of HDL-C and Apo B increased in AD patients. The dyslipidemia in AD patients might be correlated with age, but not sex and Apo E genotypes.

Influence of ApoE gene polymorphisms on therapeutic effects of lipid-lowering statins among patients with ischemic cerebral infarction / 中华医学遗传学杂志

OBJECTIVE@#To assess the influence of apolipoprotein E (ApoE) gene polymorphisms on the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction.@*METHODS@#One hundred and six patients with ischemic cerebral infarction who orally took lipid-lowering statins for 3 months were enrolled. Changes in serum triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) before and after the drug administration were analyzed. ApoE gene polymorphisms were detected by real-time fluorescent quantitative PCR, and genotypes of ApoE gene in patients with different effects were compared.@*RESULTS@#The detection rates for E2/E2, E2/E3, E3/E3, E2/E4 and E3/E4 genotypes were 0.94%, 11.32%, 63.21%, 1.89% and 22.64%, respectively. And the detection rates for E2, E3 and E4 alleles were 7.55%, 80.19% and 12.26%, respectively. Biochemical phenotypes included E2 type (13 cases, 12.26%), E3 type (69 cases, 65.09%) and E4 type (24 cases, 22.65%). Before administration, TG and TC of E2 type were the highest (P<0.05), but no significant difference was detected in HDL-C and LDL-C among the three phenotypes (P>0.05).Following the drug administration, TG, TC and LDL-C were decreased, while HDL-C was increased. HDL-C of E2 type was the highest, TC and LDL-C of E4 type were the highest (P<0.05). The E3/E3 ratio in low-efficiency group at admission was lower than that in the high-efficiency group, while the E3/E4 ratio was higher than that in the high-efficiency group (P<0.05). The proportion of E3 allele in low-efficiency group was lower than that in high-efficiency group, while the proportion of E4 allele was higher than that in high-efficiency group (P<0.05).@*CONCLUSION@#ApoE gene polymorphisms are closely correlated with the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. The lipid-lowering effects are more significant in patients with E2 and E3 genotypes, but were poor in those with the E4 genotype. Personalized regimens should be applied.

Interaction between physical exercise and APOE gene polymorphism on cognitive function in older people

We aimed to present an overview of the literature regarding the interaction between physical exercise and APOE gene polymorphism on cognitive function, particularly in patients with Alzheimer's disease (AD). Firstly, this review focused on the effect of the physical exercise on cognitive function, regardless of APOE gene polymorphism. Some studies have shown that a high level of cardiorespiratory fitness is associated with less neuronal damage with an improvement in memory score tests whereas other studies failed to detect any association between physical exercise and cognitive improvement either in healthy individuals or patients with AD. Taken together, standardized protocols and more longitudinal studies are required to provide a better insight into the effects of physical exercise on cognitive function. Although there is no agreement in the literature regarding the effects of physical exercise on cognitive function, it is well established that it improves social interaction and the feeling of well-being, thereby positively contributing to the quality of life of the elderly. Regarding the influence of physical exercise on cognitive function in APOE ε4 allele carriers, the data trend shows that the carriers of allele ε4 for APOE gene were more responsive to the beneficial effects of physical exercise on cognitive function compared with non-carriers. Nevertheless, studies with larger sample sizes will provide more accuracy about this relationship.

Study on effect of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" on atherosclerosis in ApoE~(-/-) mice based on liver metabonomics / 中国中药杂志

In this study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS)-based liver metabolomics approach was used to explore the mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in improving atherosclerosis(AS) of mice with apolipoprotein E gene knockout(ApoE~(-/-)). AS mouse model was induced by high-fat diet. The pathological and biochemical indexes such as the histopathological changes, body weight, liver weight, blood lipid level and inflammatory factors in the liver of mice were determined. The metabolic profiling of mice liver samples was performed with UPLC-Q-TOF-MS. Multiple statistical analysis methods including partial least squares discriminant analysis(PLS-DA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were employed to screen and identify biomarkers. The levels of related enzymes including LCAT, sPLA2, EPT1 and ACER1 were detected. The results showed that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" significantly reduced the areas of aortic plaque and fat vacuoles of liver in AS mice and decreased the accumulation of lipid droplets and liver coefficient. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" also regulated the levels of blood lipid and inflammatory injury in the liver. The metabolites of the control group, the model group and the "Trichosanthis Fructus-Allii Macrostemonis Bulbus" group could be distinguished significantly. Fifteen potential biomarkers related to AS were discovered and preliminarily identified, seven of which could be regulated by "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in a trend of returning to normal. Metabolic pathway analysis screened out two major metabolic pathways. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" obviously regulated the levels of LCAT, sPLA2, EPT1 and ACER1. It was inferred that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" could play a major role in AS treatment by regulating glycerophospholipid and sphingolipid metabolism disorders in the liver, with the mechanism probably relating to the intervention of the expression of LCAT, sPLA2, EPT1 and ACER1.

Short-chain fatty acid butyrate acid attenuates atherosclerotic plaque formation in apolipoprotein E-knockout mice and the underlying mechanism / 生理学报

This study was designed to evaluate the role of short-chain fatty acid butyrate acid on intestinal morphology and function, and atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE

Association of

INTRODUCTION@#The apolipoprotein E (@*METHODS@#We classified the @*RESULTS@#The baseline serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lower in carriers of @*CONCLUSION@#Polymorphism in the

Naringenin promotes cell autophagy to improve high-fat-diet-induced atherosclerosis in ApoE-/- mice

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.

Inhibition of CXCR2 alleviates the development of abdominal aortic aneurysm in Apo E-/- mice

ABSTRACT Purpose To investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2). Methods Mouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1β and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining. Results We found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1β and TNF-α, which were then partly abolished by SB225002. Conclusions CXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.

Frecuencias genotípicas y alélicas de apolipoproteina e (APOE) en una muestra de adultos en Bogotá / Genotypic and allelic frequencies of apolipoprotein e (APOE) in a sample of adults in bogotá

Introducción: la apolipoproteína E (APOE) es una glicoproteína implicada en el transporte de moléculas lipídicas. Se han descrito tres alelos del gen APOE: Ɛ2, Ɛ3 y Ɛ4. Varios estudios demuestran asociación de la isoforma APOE4 con Alzheimer de inicio tardío. Objetivos: determinar las frecuencias genotípicas y alélicas del gen APOE en una muestra de adultos en Bogotá. Materiales y métodos: estudio observacional descriptivo de corte transversal. A partir de una muestra de sangre periférica se extrajo ADN genómico y se realizó PCR-Tetraprimer para la determinación de los alelos de APOE. Resultados: se incluyeron 1.254 sujetos, 942 mujeres (75%) y 312 hombres (25%) con edades entre 40 y 100 años. El alelo más frecuente fue el Ɛ3 (85%), seguido por Ɛ4 (11%) y Ɛ2 (2%). De la población que manifestó tener ascendencia cundiboyacense, 567 sujetos (74.6%) presentaban el genotipo Ɛ3/Ɛ3, mientras que 156 (20.4%) el Ɛ3/Ɛ4, 23 (3%) el Ɛ2/Ɛ3, 11 (1.5%) el Ɛ4/Ɛ4y 4 (0.5%) el Ɛ2/Ɛ4. Los individuos con genotipoƐ2/Ɛ2 manifestaron no conocer el dato de ascendencia. Conclusiones: las frecuencias alélicas y genotípicas de APOE varían según el origen étnico, sin embargo es posible la identificación de sujetos con el genotipo menos frecuente (Ɛ2/Ɛ2) al analizar muestras de mayor tamaño. En los reportes previos en el país no se ha descrito el genotipo Ɛ2/Ɛ2, el cual fue identificado en la presente muestra como el de menor proporción.

Introduction:apolipoprotein E (APOE) is a glycoprotein involved in the transport of lipid molecules. Three alleles of the APOE gene have been described: Ɛ2, Ɛ3 and Ɛ4. Several studies show an association of the APOE isoform with late-onset Alzheimer ́s disease. Objectives: to determine the genotypic and allelic frequencies of the APOE gene in an adult sample in Bogotá. Materials and Methods: a cross-sectionalobservational descriptive study. Genomic DNA was extracted from a peripheral blood sample and APOE alleles and genotypes were determined using the PCR tetra-primer method. Results:we included 1254 subjects, 942 women (75%) and 312 men (25%) aged between 40 and 100 years. The most frequent allele was Ɛ3 (85%), followed by Ɛ4 (11%) and Ɛ2 (2%). Of the population that declared to have Cundinamarca and Boyacá sub-regions ancestry, 567 subjects (74.6%) had genotype Ɛ3/Ɛ3, while 156 (20.4%) hadƐ3/Ɛ4, 23 (3%) Ɛ2/Ɛ3, 11 (1.5%) Ɛ4/Ɛ4and 4 (0.5%) had genotype Ɛ2/Ɛ4.The individuals with genotype Ɛ2/Ɛ2 declared not to know the data on their ancestry. Conclusions: the allelic and genotypic frequencies of APOE vary according to ethnic origin. However identifying subjects with the less frequent genotype (Ɛ2/Ɛ2) is possible when analyzing larger samples. In previous reports in the country, genotype Ɛ2/Ɛ2, has not been described and was identified in the present sample as the one with the lowest proportion.

Associação de Fatores de Risco Cardiovascular e Polimorfismo de APOE com Mortalidade em Idosos Longevos: Uma Coorte de 21 Anos / Association of Cardiovascular Risk Factors and APOE Polymorphism with Mortality in the Oldest Old: A 21-Year Cohort Study

Resumo Fundamento: O conhecimento dos fatores ambientais e genéticos para um envelhecimento bem-sucedido em idosos longevos é controverso. Acrescenta-se a esta evidência, o fato de serem poucos os estudos delineados com essa população. Objetivo: Investigar a relação entre os genótipos mais frequentes da apolipoproteína E (APOE) e a mortalidade em idosos longevos que vivem em comunidade e sua sobrevida de acordo com os fatores de risco cardiovascular. Métodos: Uma amostra de 74 idosos com 80 anos ou mais da coorte do Projeto Veranópolis foi selecionada para genotipagem da APOE. Na linha de base, foram coletadas variáveis antropométricas, dosagens sanguíneas de glicose e lipídeos, pressão arterial e variáveis de estilo de vida (tabagismo, consumo de álcool e atividade física). A escala Bayer de Atividades da Vida Diária foi aplicada aos cuidadores dos idosos. O tempo de seguimento total do estudo foi 21 anos. Um p<0,05 bicaudal foi considerado estatisticamente significativo. Resultados: Não encontramos associação entre os genótipos da APOE e mortalidade. Entretanto, o risco de morte em idosos fumantes foi 2,30 vezes (hazard ratio [HR]; intervalo de confiança de 95% [IC 95%] 1,01 a 5,24); em diabéticos, 3,95 vezes (HR; IC 95% 1,27 a 12,30) do risco dos não diabéticos. Indivíduos que praticavam atividade física vigorosa tiveram uma redução no risco de óbito em 51% (HR = 0,49; IC 95% 0,27 a 0,88). Para o aumento de 1 mmHg na pressão arterial sistólica houve uma redução de 2% (HR = 0,98; IC 95% 0,97 a 0,99) no risco de morte. Conclusão: Nesta amostra de longevos, não houve associação entre os genótipos da APOE e mortalidade. Entretanto, os fatores de risco cardiovasculares clássicos podem ser importantes para a mortalidade geral em pessoas muito idosas.

Abstract Background: Knowledge of environmental and genetic factors for healthy aging in elderly people is controversial. In addition to this evidence, few studies have been designed for this population. Objectives: To investigate the relationship between the most frequent apolipoprotein E (APOE) genotypes and mortality in very elderly individuals living in a community and to evaluate survival according to cardiovascular risk factors. Methods: A sample of 74 elderly individuals aged ≥ 80 years, from the Veranópolis Project cohort, was selected for APOE genotyping. At baseline, anthropometric variables, glucose and lipid levels, blood pressure, and lifestyle variables (smoking, alcohol consumption, and physical activity) were collected. The Bayer Activities of Daily Living Scale was applied to their caregivers. Total study follow-up was 21 years. Two-sided p < 0.05 was considered statistically significant. Results: There was no association between APOE genotypes and mortality. However, the risk of death in elderly smokers was 2.30 times higher (hazard ratio [HR], 95% CI 1.01 to 5.24); in individuals with diabetes, it was 3.95 times higher (HR, 95% CI 1.27 to 12.30) than in individuals without diabetes. Subjects who practiced vigorous physical activity had a 51% reduction in risk of death (HR = 0.49, 95% CI 0.27 to 0.88). For an increase of 1 mmHg in systolic blood pressure, there was a 2% reduction (HR = 0.98, 95% CI 0.97 to 0.99) in risk of death. Conclusion: In this sample population, APOE genotypes were not associated with mortality. However, classic cardiovascular risk factors may be important for overall mortality in the very elderly.

Characterization of patients with early vs. late-onset Alzheimers dementia / Caracterización de pacientes con demencia de tipo Alzheimer precoz vs tardío

Introduction: Alzheimer's dementia (AD) has an early and a late onset. More information is needed regarding risk factors according to the age of onset of AD. The objective is to characterize the sociodemographic, anthropometric, laboratory and genetic variables as well as the history of patients with ade novodiagnosis of AD, by age of onset, at the Hospital Universitario C.A.R.I.'s mental health site over a period of two years. Methods: a cross-sectional descriptive study of 39 patients with ade novodiagnosis of AD. A questionnaire was completed, paraclinical studies were ordered and a blood sample was obtained for APOE genotyping. The IBM SPSS 21 software was used for analysis. Results: 82.05% had late-onset and 17.95% had early-onset AD. Of those with early-onset AD, 57.14% were females, as were 71.90% of those with late-onset AD. 71.44% of those with early-onset AD were married and 53.12% with late-onset AD were widowed. Only 14.29% with early-onset and 18.75% with late-onset AD had optimal LDL levels. Altogether, 79.49% of the population was heterozygous for the ε4 allele. 71.43% of those with early-onset AD had a family history of dementia. Discussion: age is the main factor associated with AD and females were more frequent in both groups. Social relationships play a role in early detection of symptoms. Lipid profile abnormalities were seen in both groups. Having at least one ε4 allele is a frequent finding in AD. Having a first-degree relative with dementia and/or Alzheimer's was more frequent in early-onset AD.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1316).

Introducción: la demencia de tipo Alzheimer (DTA) tiene presentación precoz o tardía. Es necesaria mayor información sobre factores de riesgo según edad de aparición de DTA. El objetivo es caracterizar variables sociodemográficas, antropométricas, de laboratorio, genéticas y antecedentes en pacientes con diagnósticode novode DTA según edad de aparición en el Hospital Universitario C.A.R.I. sede salud mental en un periodo de dos años. Metodología: estudio descriptivo transversal con 39 pacientes con diagnósticode novode DTA. Se realizó un cuestionario, solicitaron paraclínicos y se obtuvo una muestra sanguínea para genotipificación deAPOE.Se utilizó el software IBM SPSS 21 para análisis. Resultados: el 82.05% tenían DTA tardío y 17.95% DTA precoz. El 57.14% con DTA precoz y 71.90% con DTA tardía eran de sexo femenino. El 71.44% con DTA precoz eran casados y 53.12% con DTA tardío eran viudos. Solo 14.29% con DTA precoz y 18.75% con DTA tardío tenían niveles óptimos de LDL. El 79.49% de la población era heterocigoto para el alelo ε4. El 71.43% con DTA precoz tenía antecedente familiar de demencia. Discusión: la edad es el principal factor asociado a DTA y el sexo femenino fue más frecuente en ambos grupos. Las relaciones sociales juegan un rol en la identificación temprana de la sintomatología. Las alteraciones del perfil lipídico se evidenciaron en ambos grupos. Tener al menos un alelo ε4 es un hallazgo frecuente de DTA. Tener un familiar con demencia y/o Alzheimer de primer grado de consanguinidad fue más frecuente en DTA precoz.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1316).

Phenotype of definite familial hypercholesterolemia with negative genetic study in Argentina / Fenotipo de hipercolesterolemia familiar definitivo con estudio genético negativo en Argentina

Abstract Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.

Resumen Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.

Effect of Porphyromonas gingivalis infection on atherosclerosis in apolipoprotein-E knockout mice / 北京大学学报(医学版)

OBJECTIVE@#Studies have indicated that periodontal pathogen Porphyromonas gingivalis (P. gingivalis) infection may contributed to accelerate the development of atherosclerosis. The aim of this study was to investigate the effect of inflammation, oxidative stress and the mechanism on atherosclerosis in apolipoprotein-E knockout (ApoE-/-) mice with P. gingivalis infection.@*METHODS@#Eight-week-old male ApoE-/- mice (C57BL/6) were maintained under specific pathogen-free conditions and fed regular chow and sterile water after 1 weeks of housing. The animals were randomly divided into two groups: (a) ApoE-/- + PBS (n=8); (b) ApoE-/- + P.gingivalis strain FDC381 (n=8). Both of the groups received intravenous injections 3 times per week for 4 weeks since 8 weeks of age. The sham control group received injections with phosphate buffered saline only, while the P. gingivalis-challenged group with P.gingivalis strain FDC381at the same time. After 4 weeks, oxidative stress mediators and inflammation cytokines were analyzed by oil red O in heart, Enzyme linked immunosorbent assay (ELISA) in serum, quantitative real-time PCR and Western blot in aorta.@*RESULTS@#In our study, we found accelerated development of atherosclerosis and plaque formation in aorta with oil red O staining, increased oxidative stress markers [8-hydroxy-2-deoxyguanosine (8-OHdG), NADPH oxidase (NOX)-2 and NOX-4], as well as increased inflammation cytokines [interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α)] in the serum and aorta of the P. gingivalis-infected ApoE-/- mice. Compared with the control group, there was a significant increase protein level of nuclear factor-kappa B (NF-κB) in aorta after P. gingivalis infection.@*CONCLUSIONS@#Our results suggest that chronic intravenous infection of P. gingivalis in ApoE-/- mice could accelerate the development of atherosclerosis by disturbing the lipid profile and inducing oxidative stress and inflammation. The NF-κB signaling pathway might play a potential role in the P. gingivalis-accelerated atherogenesis.

Pathogenesis, histopathologic findings and treatment modalities of lipoprotein glomerulopathy: A review / Patogênese, achados histopatológicos e modalidades de tratamento da glomerulopatia por lipoproteínas: Uma revisão

Abstract Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE.

Resumo A glomerulopatia por lipoproteínas (GLP) é uma patologia rara que causa síndrome nefrótica e/ou insuficiência renal. Na microscopia, a GLP é caracterizada pela presença de trombos de lipoproteínas em capilares glomerulares dilatados devido a diferentes mutações no gene da ApoE. O gene da ApoE está localizado no cromossomo 19q13.2 e pode ser identificado em quase todas as lipoproteínas séricas. A ApoE age como fator de proteção na arterioesclerose por conta de sua interação com a depuração de lipoproteínas mediada por receptores e com o receptor de colesterol. Dentre os polimorfismos mais comuns destacam-se ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3 e ApoE4/4. A GLP pode acometer indivíduos de todas as faixas etárias, com discreta predominância do sexo masculino. Pacientes afetados tipicamente apresentam dislipidemia, hiperlipoproteinemia tipo III e proteinúria. O tratamento da GLP é conduzido com fenofibrato, antilipêmicos, corticosteroides, LDL-aferese, troca de plasma, antiplaquetários, anticoagulantes, uroquinase e transplante renal. Recidiva no enxerto renal indica a existência de componentes patogênicos do complexo humoral extraglomerular resultante de metabolismo lipoproteico anômalo, possivelmente associado a ApoE.

Effects of a 12-week high intensity interval training on blood lipid of dyslipidemia patients with different apolipoprotein E genotypes / 中国应用生理学杂志

OBJECTIVE@#To evaluate the effects of 12 weeks high intensity interval training(HIIT) on serum lipids profile in patients with dyslipidemia of different apolipoprotein E(ApoE) genotypes.@*METHODS@#Eighty-eight patients with dyslipidemia were screened by fasting blood lipid as subjects. Apolipoprotein E genotypes were detected in oral mucosa of subjects. Serum lipids before and after 12 weeks high intensity interval training were measured to analysis the effect of high intensity interval training on serum lipids.@*RESULTS@#Five genotypes were detected in 88 cases of dyslipidemia. The distributions were ApoE3/3＞ApoE3/4＞ApoE2/3＞ApoE2/2＞ApoE2/4,and allele ε3＞ε2=ε4. Before exercise intervention, the level of total cholesterol in patients with ε4 allele was significant higher than those in patients with ε2 and ε3 (P＜0.01), low density lipoprotein cholesterol in patients with ε4 was significant higher than that of patients with ε2 (P＜0.05), and the other indexes had no significant difference among the groups (P＞ 0.05). After 12 weeks high intensity interval training, the levels of total cholesterol, triglyceride and low density lipoprotein cholesterol were decreased significantly ,while the level of high density lipoprotein cholesterol was increased in those patients with ε3 genotype. For those individuals with ε4 genotype , their serum levels of total cholesterol and low density lipoprotein cholesterol were reduced after 12 weeks high intensity interval training , but there was no changes in serum levels of triglyceride and high density lipoprotein cholesterol. For those individuals with ε2 genotype, there was no significant improvement in serum lipids after 12 weeks high intensity interval training interventions.@*CONCLUSION@#The polymorphisms of apolipoprotein E gene resulted in different effects of exercise interventions on serum lipids of dyslipidemia. Twelve weeks high intensity interval training can be used as an intervention method to regulate serum lipids of dyslipidemia with ε3 and ε4 alleles.