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APOE ɛ4 Is Associated with Postprandial Inflammation in Older Adults with Metabolic Syndrome Traits.
Schönknecht, YB, Crommen, S, Stoffel-Wagner, B, Coenen, M, Fimmers, R, Stehle, P, Ramirez, A, Egert, S
Nutrients. 2021;(11)
Abstract
The apolipoprotein E (APOE) polymorphism impacts blood lipids and biomarkers of oxidation and inflammation, contributing to an isoform-dependent disease risk. We investigated the effect of the APOE genotype on postprandial metabolism after consumption of three different isoenergetic (4200 kJ) meals in older adults with a CVD risk phenotype. In a randomized crossover study, participants with metabolic syndrome traits (APOE E3, n = 39; E4, n = 10; mean age, 70 ± 5 years; BMI 31.3 ± 3.0 kg/m2) consumed a Western-like diet high-fat (WDHF), Western-like diet high-carbohydrate (WDHC), or Mediterranean-like diet (MED) meal. Parameters of lipid and glucose metabolism, inflammatory, and oxidative parameters were analyzed in blood samples collected at fasting and 1-5 h postprandially. Data were analyzed by linear mixed models. The magnitude of the IL-6 increase after the WDHF meal was significantly higher in E4 than in E3 carriers (iAUC: E4 = 7.76 vs. E3 = 2.81 pg/mL × h). The time to detect the IL-6 increase was shorter in the E4 group. All meals produced postprandial glycemia, insulinemia, and lipidemia, without differences between the E3 and the E4 groups. IL-1β and oxidized LDL levels did not change postprandially. In conclusion, APOE E4 carriers display increased postprandial inflammation, indicated by higher postprandial IL-6 increase, when compared to non-carriers.
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Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer's Disease Cooperative Study-Sponsored DHA Clinical Trial.
Tomaszewski, N, He, X, Solomon, V, Lee, M, Mack, WJ, Quinn, JF, Braskie, MN, Yassine, HN
Journal of Alzheimer's disease : JAD. 2020;(3):975-990
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Abstract
BACKGROUND Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer's disease (AD) pathogenesis and neuroinflammation. Carrying the APOEɛ4 allele (APOE4) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. OBJECTIVE We sought to clarify the effect of APOEɛ4/ɛ4 on both the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. METHODS Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n = 86) and lumbar punctures (n = 53). RESULTS After the intervention, DHA-treated APOEɛ3/ɛ3 and APOEɛ2/ɛ3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ4/ɛ4 carriers. APOEɛ2/ɛ3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ4/ɛ4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. CONCLUSION The lower increase in plasma DHA/AA and EPA/AA in APOEɛ4/ɛ4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.
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Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.
Wang, Y, Hernandez, G, Mack, WJ, Schneider, LS, Yin, F, Brinton, RD
Menopause (New York, N.Y.). 2020;(1):57-65
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Abstract
OBJECTIVE PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.
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APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.
Rasmussen, PM, Aamand, R, Weitzberg, E, Christiansen, M, Østergaard, L, Lund, TE
NeuroImage. Clinical. 2019;:101955
Abstract
Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.
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Site-Specific Glycoprofiles of HDL-Associated ApoE are Correlated with HDL Functional Capacity and Unaffected by Short-Term Diet.
Zhu, C, Wong, M, Li, Q, Sawrey-Kubicek, L, Beals, E, Rhodes, CH, Sacchi, R, Lebrilla, CB, Zivkovic, AM
Journal of proteome research. 2019;(11):3977-3984
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Since high-density lipoprotein (HDL) glycoprofiles are associated with HDL functional capacity, we set out to determine whether diet can alter the glycoprofiles of key HDL-associated proteins, including ApoE, a potent driver of chronic disease risk. Ten healthy subjects consumed a fast food (FF) and a Mediterranean (Med) diet for 4 days in randomized order, with a 4-day wash-out between treatments. A multiple reaction monitoring method was used to characterize the site-specific glycoprofiles of HDL proteins, and HDL functional capacity was analyzed. We describe for the first time that ApoE has 7 mucin-type O-glycosylation sites, which were not affected by short-term diet. The glycoprofiles of other HDL-associated proteins were also unaffected, except that a disialylated ApoC-III glycan was enriched after Med diet, and a nonsialylated ApoC-III glycan was enriched after FF diet. Twenty-five individual glycopeptides were significantly correlated with cholesterol efflux capacity and 21 glycopeptides were correlated with immunomodulatory capacity. Results from this study indicate that the glycoprofiles of HDL-associated proteins including ApoE are correlated with HDL functional capacity but generally unaffected by diet in the short term, except ApoC-III sialylation. These results suggest that HDL protein glycoprofiles are affected by both acute and long-term factors and may be useful for biomarker discovery.
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Dietary unsaturated fat increases HDL metabolic pathways involving apoE favorable to reverse cholesterol transport.
Morton, AM, Furtado, JD, Mendivil, CO, Sacks, FM
JCI insight. 2019;(7)
Abstract
BACKGROUND HDL that contains apolipoprotein E (apoE) is a subspecies especially active in steps in reverse cholesterol transport, a process that brings cholesterol from peripheral cells to the liver. Here, we studied the effect of dietary unsaturated fat compared with carbohydrate on the metabolism of HDL containing apoE. METHODS We enrolled 9 adults who were overweight or obese and had below-average HDL-cholesterol in a crossover study of a high-fat diet, primarily unsaturated, and a low-fat, high-carbohydrate diet. A metabolic tracer study was performed after each diet period. RESULTS Dietary fat increased the secretion, metabolism, and clearance of HDL subspecies containing apoE. Dietary fat increased the rate of clearance of large cholesterol-rich HDL containing apoE and increased their conversion to small HDL containing apoE, indicating selective cholesterol ester delivery to the liver. The high-unsaturated-fat diet did not affect the metabolism of HDL lacking apoE. CONCLUSION HDL containing apoE is a diet-responsive metabolic pathway that renders HDL more biologically active in reverse cholesterol transport. This may be a mechanism by which unsaturated fat protects against coronary heart disease. Protein-based HDL subspecies such as HDL containing apoE may be used to identify additional atheroprotective treatment targets not evident in the total HDL-cholesterol measurement. TRIAL REGISTRATION ClinicalTrials.gov NCT01399632. FUNDING NIH and the National Center for Advancing Translational Science.
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Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial.
Ji, T, Zhao, Y, Wang, J, Cui, Y, Duan, D, Chai, Q, Zhang, H, Liu, Z
Journal of the American Medical Directors Association. 2018;(11):995-1002.e4
Abstract
OBJECTIVES To investigate the effect of low-dose statins and apolipoprotein E (APOE) genotypes on cerebral small vessel disease (CSVD) to prevent CSVD in older hypertensive patients. DESIGN A subgroup analysis of a randomized clinical trial. SETTING Shandong area, China. PARTICIPANTS Hypertensive patients aged ≥60 years were recruited from April 2008 to November 2010. MEASUREMENTS Patients were randomly assigned to rosuvastatin (10 mg/day) or placebo groups. APOE genotypes were categorized as ε4 carriers and non-ε4 carriers. White matter hyperintensities (WMH), Fazekas scale, lacunes, and microbleeds were assessed. RESULTS After an average of intervention period of 61.8 months, WMH volume increased 1.45 ± 0.52 mL. There were 107 new-incident Fazekas scale ≥2, 65 new-incident lacunes, and 63 new-incident microbleeds. The increase in WMH volume was significantly lower in the rosuvastatin group than in the placebo group and was higher in APOE ε4 carriers than in non-ε4 carriers (all adjusted P < .001). The risk of new-incident Fazekas scale ≥2 was higher in the placebo group than in the rosuvastatin group (hazard ratio 2.150, 95% confidence interval 1.443-3.203; P < .001). APOE ε4 carriers were associated with an increased risk of new-incident Fazekas scale ≥2 compared with non-ε4 carriers (hazard ratio 1.973, 95% confidence interval 1.334-2.920; P = .001). There were no statistically significant differences in the risk of new-incident cerebral microbleeds between the rosuvastatin and placebo groups or between APOE ε4 carriers and non-ε4 carriers. There were no significant interactions between rosuvastatin use and APOE ε4 status regarding increased WMH volume (F = 1.020, P = .313) or for new-incident Fazekas scale ≥2 (P = .377), lacunes (P = .232), and microbleeds (P = .362). CONCLUSIONS/IMPLICATIONS Low-dose rosuvastatin is an effective and safe therapy for CSVD. The presence of APOE ε4 allele may not be able to predict rosuvastatin treatment outcomes for preventing and/or treating CSVD in older hypertensive patients.
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APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome.
Fallaize, R, Carvalho-Wells, AL, Tierney, AC, Marin, C, Kieć-Wilk, B, Dembińska-Kieć, A, Drevon, CA, DeFoort, C, Lopez-Miranda, J, Risérus, U, et al
Scientific reports. 2017;(1):6274
Abstract
Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.
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APOE and CETP TaqIB polymorphisms influence metabolic responses to Hibiscus sabdariffa L. and Gynostemma pentaphyllum Makino tea consumption in hypercholesterolemic subjects.
Jeenduang, N, Sangkaew, B, Chantaracha, P, Chanchareonsri, S, Plyduang, T, Thitdee, W, Samae, C, Pitumanon, W
Asia Pacific journal of clinical nutrition. 2017;(2):368-378
Abstract
BACKGROUND AND OBJECTIVES Hibiscus sabdariffa L. (HS) and Gynostemma pentaphyllum Makino (GP) have been used as traditional medicines to treat diabetes and hypercholesterolemia. Nevertheless, there is interindividual variation in the metabolic responses to HS and GP consumption. This may be due to genetic factors. The aim of this study was to investigate the effects of HS and GP tea consumption on anthropometric data, fasting blood glucose (FBG), and lipid concentrations in hypercholesterolemia subjects with different genotypes of the APOE and CETP TaqIB polymorphisms. METHODS AND STUDY DESIGN Forty-eight subjects with hypercholesterolemia were given either HS or GP tea for 30 days. Anthropometric and biochemical variables were determined, and APOE and CETP TaqIB polymorphisms were analyzed using the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). RESULTS E4 (p=0.008) and homozygous B1B1 (p=0.010) carriers had significantly decreased HDL-C concentrations after HS consumption; in addition, B2 carriers who consumed HS showed significantly decreased triglyceride (TG) concentrations (p=0.039). Regarding GP consumption, non-E4 carriers had significantly decreased HDL-C (p=0.009) and FBG (p=0.042) concentrations. Furthermore, B2 carriers had significantly decreased total cholesterol (TC) (p=0.045), HDL-C (p=0.004), and FBG (p=0.026) concentrations. CONCLUSIONS HS consumption may have beneficial effects with respect to TG concentrations in the B2 carriers, but it may adversely affect HDL-C concentrations in homozygous B1B1 and E4 carriers. In contrast, GP consumption may have favorable effects on TC and FBG concentrations but not on HDL-C concentrations for B2 and/or non-E4 carriers.
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Soy milk powder supplemented with phytosterol esters reduced serum cholesterol level in hypercholesterolemia independently of lipoprotein E genotype: a random clinical placebo-controlled trial.
Dong, S, Zhang, R, Ji, YC, Hao, JY, Ma, WW, Chen, XD, Xiao, R, Yu, HL
Nutrition research (New York, N.Y.). 2016;(8):879-84
Abstract
Phytosterols (PSs) are reported to lower the serum total cholesterol and low-density lipoprotein cholesterol concentrations enriched in some fatty foods, such as margarine. However, these high-fat foods are not very suitable for older people. Soy milk is the favorite food for elderly people in China; therefore, we hypothesized that the consumption of soy milk powder supplemented with PSs would decrease the serum cholesterol levels in older Chinese people independent of the genotypes of apolipoprotein E (ApoE). Mild to moderate hyperlipidemic patients (n = 170) were recruited from different communities and treated with placebo soy milk powder or 3.4 g PS esters-enriched soy milk powder (2.0 g/d free PS in 30 g soy milk powder). The fasting serum lipid profiles at the baseline and after 3 and 6 months of intervention were measured. The ApoE genotype was also determined. After 3 months of PS intervention, the serum lipid profile was not changed significantly in either group. The serum total cholesterol, low-density lipoprotein cholesterol, and non- high-density lipoprotein cholesterol levels decreased by 9.3%, 11.4%, and 12.6%, respectively, in the PS group at the end of the intervention (6 months) compared with the control group, whereas the serum high-density lipoprotein cholesterol and triglyceride levels were not affected significantly. In the PS group, both the ApoE3 and ApoE4 carriers had a similar response to PS consumption. These findings suggested that PS-fortified soy milk powder was effective in lowering the serum cholesterol levels in older Chinese volunteers with mild to moderate hypercholesterolemia in both the ApoE3 and ApoE4 carriers.