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1.
Association of APOE ε4 genotype and lifestyle with cognitive function among Chinese adults aged 80 years and older: A cross-sectional study.
Jin, X, He, W, Zhang, Y, Gong, E, Niu, Z, Ji, J, Li, Y, Zeng, Y, Yan, LL
PLoS medicine. 2021;(6):e1003597
Abstract
BACKGROUND Apolipoprotein E (APOE) ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease (AD), while lifestyle factors such as smoking, drinking, diet, and physical activity also have impact on cognition. The goal of the study is to investigate whether the association between lifestyle and cognition varies by APOE genotype among the oldest old. METHODS AND FINDINGS We used the cross-sectional data including 6,160 oldest old (aged 80 years old or older) from the genetic substudy of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) which is a national wide cohort study that began in 1998 with follow-up surveys every 2-3 years. Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score less than 18. Healthy lifestyle profile was classified into 3 groups by a composite measure including smoking, alcohol consumption, dietary pattern, physical activity, and body weight. APOE genotype was categorized as APOE ε4 carriers versus noncarriers. We examined the associations of cognitive impairment with lifestyle profile and APOE genotype using multivariable logistic regressions, controlling for age, sex, education, marital status, residence, disability, and numbers of chronic conditions. The mean age of our study sample was 90.1 (standard deviation [SD], 7.2) years (range 80-113); 57.6% were women, and 17.5% were APOE ε4 carriers. The mean MMSE score was 21.4 (SD: 9.2), and 25.0% had cognitive impairment. Compared with those with an unhealthy lifestyle, participants with intermediate and healthy lifestyle profiles were associated with 28% (95% confidence interval [CI]: 16%-38%, P < 0.001) and 55% (95% CI: 44%-64%, P < 0.001) lower adjusted odds of cognitive impairment. Carrying the APOE ε4 allele was associated with 17% higher odds (95% CI: 1%-31%, P = 0.042) of being cognitively impaired in the adjusted model. The association between lifestyle profiles and cognitive function did not vary significantly by APOE ε4 genotype (noncarriers: 0.47 [0.37-0.60] healthy versus unhealthy; carriers: 0.33 [0.18-0.58], P for interaction = 0.30). The main limitation was the lifestyle measurements were self-reported and were nonspecific. Generalizability of the findings is another limitation because the study sample was from the oldest old in China, with unique characteristics such as low body weight compared to populations in high-income countries. CONCLUSIONS In this study, we observed that healthier lifestyle was associated with better cognitive function among the oldest old regardless of APOE genotype. Our findings may inform the cognitive outlook for those oldest old with high genetic risk of cognitive impairment.
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2.
High Apolipoprotein E Levels Predict Adverse Limb Events in Patients with Peripheral Artery Disease Due to Peripheral Artery Disease Undergoing Endovascular Treatment and On-Statin Treatment.
Fukase, T, Dohi, T, Kato, Y, Chikata, Y, Takahashi, N, Endo, H, Doi, S, Nishiyama, H, Okai, I, Iwata, H, et al
International heart journal. 2021;(4):872-878
Abstract
Little is known about the association between limb prognosis in peripheral artery disease and apolipoprotein E (apoE). We evaluated the long-term impact of apoE on adverse limb events in patients with intermittent claudication receiving statin treatment.A total of 218 consecutive patients (mean age, 73 ± 8 years; 81% men) with intermittent claudication who underwent their first intervention between 2009 and 2020 were included in this study. All patients had achieved LDL-C < 100 mg/dL on statin treatment and were divided into two groups based on the apoE value (≥ 4.7 or < 4.7 mg/dL). We evaluated the incidence of major adverse limb events (MALEs), including vessel revascularization and limb ischemia development.A total of 39 and 179 patients were allocated to the higher and lower apoE groups, respectively. Compared to the lower apoE group, the higher apoE group had a significantly higher total cholesterol level, triglyceride level, and non-high-density lipoprotein cholesterol level. During the median follow-up period of 3.6 years, 30 patients (13.8%) developed MALEs. Kaplan-Meier analysis revealed that the cumulative incidence of MALEs in the higher apoE group was significantly higher than that in the lower apoE group (44.0% versus 21.6%, log-rank test, P = 0.002). During multivariable Cox hazard analysis, higher apoE level (≥ 4.7 mg/dL) (hazard ratio, 2.61; 95% confidence interval, 1.18-5.70, P = 0.019) was the only strong independent predictor of MALEs.ApoE levels could be a strong predictor and residual risk for long-term limb prognosis in patients with intermittent claudication and achieving LDL-C < 100 mg/dL with statin treatment.
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3.
Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β.
Chai, AB, Lam, HHJ, Kockx, M, Gelissen, IC
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(9):158980
Abstract
Since the identification of the apolipoprotein E (apoE) *ε4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-β (Aβ) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic Aβ peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the Aβ processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired Aβ clearance, however data regarding Aβ synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with Aβ. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform.
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4.
Differences in Recycling of Apolipoprotein E3 and E4-LDL Receptor Complexes-A Mechanistic Hypothesis.
Kim, M, Bezprozvanny, I
International journal of molecular sciences. 2021;(9)
Abstract
Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer's disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.
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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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6.
Association between the APOE gene polymorphism and lipid profile and the risk of atrial fibrillation.
Deng, X, Hou, J, Deng, Q, Zhong, Z
Lipids in health and disease. 2021;(1):123
Abstract
BACKGROUND The relationship between the APOE gene polymorphism and lipid profiles and atrial fibrillation (AF) remains controversial. The current study purposed to investigate how the APOE gene SNPs (rs429358 and rs7412) and lipid profile are associated with the risk for AF among the Hakka population in southern China. METHODS Finally, 1367 patients were enrolled in this study, including 706 participants with AF (41 ~ 98 years old, 58.64 % male) and 661 non-AF subjects (28 ~ 95 years old, 59.46 % male). The collected data included baseline characteristics, medical history, laboratory tests and echocardiography parameters. A general linear model (two-way analysis of variance (ANOVA)) and Tukey post-hoc tests were applied to identify an APOE allele, AF group, and interaction effect on lipid profiles. Logistic regression analysis was performed to identify risk factors for AF. RESULTS For AF group, the most common genotype was E3/E3 (53.82 %), followed by E3/E4 (28.19 %), E2/E3 (13.60 %), E4/E4 (1.98 %), E2/E4 (1.84 %) and E2/E2 (0.57 %). The two-way ANOVA followed by the Tukey procedure showed the following: the lipid levels depended significantly on AF and APOE allele groups for TG, TC, LDL-C and Apo-B (all P < 0.001), and statistically significant interactions between AF and APOE allele were observed in the above 4 variables (all P < 0.05). Multivariate regression analysis indicated that age ≥ 65years (P < 0.001), high diastolic blood pressure (DBP ≥ 90mm Hg, P = 0.018), a high levels of total cholesterol (TC ≥ 5.2mmol/L, P < 0.001) and triglyceride (TG ≥ 1.7mmol/L, P = 0.028), but not the two SNPs of the APOE gene (rs7412 and rs429358) (OR 1.079, P = 0.683), were significant independent risk factors for AF in the study population. CONCLUSIONS The principal findings of this study showed that individuals at high risk for AF were those over 65 years of age, higher DBP as well as high levels of TC and TG among the southern China Hakka population. The levels of TG, TC, LDL-C and Apo-B depended significantly on AF and APOE allele groups, and statistically significant interactions between AF and APOE allele were observed in the above 4 variables, although the APOE gene SNPs (rs429358 and rs7412) were no significant risk for AF incidence. Further investigation is needed to elucidate whether other SNPs of the APOE gene have a bearing on AF incidents.
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7.
Beyond the CNS: The many peripheral roles of APOE.
Martínez-Martínez, AB, Torres-Perez, E, Devanney, N, Del Moral, R, Johnson, LA, Arbones-Mainar, JM
Neurobiology of disease. 2020;:104809
Abstract
Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2, ε3, and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes.
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8.
Impact of apolipoprotein E genetic polymorphisms on liver disease: An essential review.
Nascimento, JCR, Matos, GA, Pereira, LC, Mourão, AECCB, Sampaio, AM, Oriá, RB, Toniutto, P
Annals of hepatology. 2020;(1):24-30
Abstract
Cirrhosis is an advanced stage of liver disease, compromising liver function with systemic health implications and poor quality of life. Hepatitis C virus (HCV) infection and alcoholic liver disease are the main causes of this pathology. However, since genetic factors may play a large role in the progression and severity of liver disease, and as apolipoprotein E (apoE) has been recognised to be mainly synthesised in the liver, apoE polymorphism studies are important to better understand the causal mechanisms in liver diseases. In this review, we summarise up-to-date studies addressing how apoE polymorphisms influence liver cirrhosis and liver transplantation outcomes and potential protective mechanisms. Although more clinical studies are needed to support these findings, the apoE ɛ4 allele seems to be protective against the progression of liver cirrhosis in the majority of aetiologies and the postoperative serum apoE phenotype of the transplanted subject receptors was converted to that of the donor, indicating that >90% of apoE in plasma is synthesised in the hepatic system.
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9.
Association of Apolipoprotein E gene polymorphism with Preeclampsia: a meta-analysis.
Abyadeh, M, Heydarinejad, F, Khakpash, M, Asefi, Y, Shab-Bidar, S
Hypertension in pregnancy. 2020;(2):196-202
Abstract
Objective: The aim of this meta-analysis was to examine the association of ApoE polymorphism with the risk of developing PE.Methods: A comprehensive search was carried out through PubMed, Scopus, and Embase. The ORs with corresponding 95% CIs were extracted. Fixed model was used for meta-analysis and in case of existing heterogeneity a random-effects model was applied.Results: Association of ApoE polymorphism with the risk of developing PE was not statistically significant (OR = 0.86, 95% CI: 0.67-1.11; OR = 0.92, 95%CI: 0.73-1.15, respectively for ε2 and ε4).Conclusion: ApoE polymorphism might not be associated with the risk of PE.
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10.
VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly.
Croyal, M, Blanchard, V, Ouguerram, K, Chétiveaux, M, Cabioch, L, Moyon, T, Billon-Crossouard, S, Aguesse, A, Bernardeau, K, Le May, C, et al
Arteriosclerosis, thrombosis, and vascular biology. 2020;(3):819-829
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Abstract
OBJECTIVE To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [LDLR] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9-gain-of-function and familial hypercholesterolemia-LDLR groups compared with controls and PCSK9-loss-of-function groups (14±12 versus 5±4 mg/dL; P=0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9-loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (r=0.50; P<0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (r=0.96; P<0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (r=0.83; P=0.015). In contrast, PCSK9 reduction (-35%; P=0.008) was only correlated with that of VLDL-apoE absolute production rate (r=0.79; P=0.028). CONCLUSIONS VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).