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Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed. [ABSTRACT FROM AUTHOR]

Aims The association of plasma high-density lipoprotein (HDL) cholesterol with risk of dementia is unclear. We, therefore, tested the hypothesis that high levels of plasma HDL cholesterol are associated with increased risk of dementia and whether a potential association is of a causal nature. Methods and results In two prospective population-based studies, the Copenhagen General Population Study and the Copenhagen City Heart Study (N  = 111 984 individuals), we first tested whether high plasma HDL cholesterol is associated with increased risk of any dementia and its subtypes. These analyses in men and women separately were adjusted multifactorially for other risk factors including apolipoprotein E (APOE) genotype. Second, taking advantage of two-sample Mendelian randomization, we tested whether genetically elevated HDL cholesterol was causally associated with Alzheimer's disease using publicly available consortia data on 643 836 individuals. Observationally, multifactorially adjusted Cox regression restricted cubic spline models showed that both men and women with extreme high HDL cholesterol concentrations had increased risk of any dementia and of Alzheimer's disease. Men in the 96th–99th and 100th vs. the 41st–60th percentiles of HDL cholesterol had multifactorially including APOE genotype adjusted hazard ratios of 1.66 (95% confidence interval 1.30–2.11) and 2.00 (1.35–2.98) for any dementia and 1.59 (1.16–2.20) and 1.87 (1.11–3.16) for Alzheimer's disease. Corresponding estimates for women were 0.94 (0.74–1.18) and 1.45 (1.03–2.05) for any dementia and 0.94 (0.70–1.26) and 1.69 (1.13–2.53) for Alzheimer's disease. Genetically, the two-sample Mendelian randomization odds ratio for Alzheimer's disease per 1 SD increase in HDL cholesterol was 0.92 (0.74–1.10) in the IGAP2019 consortium and 0.98 (0.95–1.00) in the ADSP/IGAP/PGC-ALZ/UKB consortium. Similar estimates were observed in sex stratified analyses. Conclusion High plasma HDL cholesterol was observationally associated with increased risk of any dementia and Alzheimer's disease, suggesting that HDL cholesterol can be used as an easily accessible plasma biomarker for individual risk assessment. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH. [Display omitted] • People with HIV had higher plasma apoE levels than controls from the general population. • Plasma apoE was consistently higher in people with HIV when stratifying by triglyceride levels. • People with HIV also had higher apoE/apoB ratio compared to controls. • Thus, the association between HIV status and apoE was independent of changes in other lipid parameters. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well‐characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. Methods: The APOE gene was sequenced in 10,369 individuals, and nine amino acid–changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. Results: Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10−4 and P = 1 × 10−4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. Discussion: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE. [ABSTRACT FROM AUTHOR]

Aims Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted. Methods and results In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22–31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50–59, 60–69, 70–79, and 80–100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively. Conclusion Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Aims To determine whether plasma apoE levels and APOE genotype are associated with all-cause and cause-specific mortality. Methods and results Using a prospective cohort design with 105 949 white individuals from the general population, we tested the association between plasma apoE at study enrolment and death during follow-up, and whether this was independent of APOE genotype. We confirmed the well-known association between APOE genotypes and mortality. For all-cause, cardiovascular, and cancer mortality, high levels of apoE were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. the fifth septile of plasma apoE, hazard ratios (HRs) were 1.20 (95% confidence interval 1.12–1.28) for all-cause mortality, 1.28 (1.13–1.44) for cardiovascular mortality, and 1.18 (1.05–1.32) for cancer mortality. Conversely, for the lowest vs. the fifth septile the HR was 1.44 (1.01–2.05) for dementia-associated mortality. Results were similar in analyses restricted to APOE ɛ33 carriers. Examining genetically determined plasma apoE, a 1 mg/dL increase conferred risk ratios of 0.97 (0.92–1.03) for cardiovascular mortality and 1.01 (0.95–1.06) for cancer mortality, while a 1 mg/dL decrease conferred a risk ratio of 1.70 (1.36–2.12) for dementia-associated mortality. Conclusion High plasma levels of apoE were associated with increased all-cause, cardiovascular, and cancer mortality, however of a non-causal nature, while low levels were causally associated with increased dementia-associated mortality. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Background: Dementia is a major cause of disability, and risk-factor reduction may have the potential to delay or prevent the disease. Our aim was to determine the absolute 10-year risk of dementia, by age, sex and apolipoprotein E (APOE) genotype.Methods: We obtained data from the Copenhagen General Population Study (from 2003 to 2014) and the Copenhagen City Heart Study (from 1991 to 1994 and 2001 to 2003). Participants underwent a questionnaire, physical examination and blood sampling at baseline. Diagnoses of dementia and cerebrovascular disease were obtained from the Danish National Patient Registry up to Nov. 10, 2014.Results: Among 104 537 individuals, the absolute 10-year risk of Alzheimer disease in 3017 women and men who were carriers of the APOE ɛ44 genotype was, respectively, 7% and 6% at age 60-69 years, 16% and 12% at age 70-79 years, and 24% and 19% at age 80 years and older. Corresponding values for all dementia were 10% and 8%, 22% and 19%, and 38% and 33%, respectively. Adjusted hazard ratios (HRs) for all dementia increased by genotype, from genotype ɛ22 to ɛ32 to ɛ33 to ɛ42 to ɛ43 to ɛ44 (p for trend < 0.001). Compared with ɛ33 carriers, ɛ44 carriers were more likely to develop Alzheimer disease (adjusted HR 8.74, 95% confidence interval [CI] 7.08-10.79), vascular dementia (adjusted HR 2.87, 95% CI 1.54-5.33), unspecified dementia (adjusted HR 4.68, 95% CI 3.74-5.85) and all dementia (adjusted HR 5.77, 95% CI 4.89-6.81).Interpretation: Age, sex and APOE genotype robustly identify high-risk groups for Alzheimer disease and all dementia. These groups can potentially be targeted for preventive interventions. [ABSTRACT FROM AUTHOR]

Introduction: In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. Methods: Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively. Results: In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10−17 and 9 × 10−21). APOE‐weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10−300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27–1.57) for Alzheimer's disease and 1.33 (1.25–1.43) for all dementia (F‐statistics = 3821). Discussion: Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship. Highlights: Observationally low plasma apolipoprotein E is associated with risk of dementia.We studied 106,562 and 75,260 individuals using a Mendelian randomization approach.Genetically low plasma apolipoprotein E is associated with high risk of dementia.Taken together the observational and genetic estimates suggest a causal relationship. [ABSTRACT FROM AUTHOR]

Introduction The adenosine triphosphate-binding cassette transporter A1 ( ABCA1 ) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways. Methods We tested whether a loss-of-function mutation in ABCA1 , N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. Results N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE ( P = 1 × 10 −11 ). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32–12.9) for AD, 2.46 (1.10–5.50) for cerebrovascular disease, and 8.28 (2.03–33.7) for the hemorrhagic stroke subtype. Discussion A loss-of-function mutation in ABCA1 , present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population. [ABSTRACT FROM AUTHOR]

Background At the APOE gene, encoding apolipoprotein E, genotypes of the &varepsilon;2/&varepsilon;3/&varepsilon;4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk.Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT).Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84–1.43) for &varepsilon;2/&varepsilon;2; 0.85 (95% CrI: 0.78–0.92) for &varepsilon;2/&varepsilon;3; 1.05 (95% CrI: 0.89–1.24) for &varepsilon;2/&varepsilon;4; 1.05 (95% CrI: 0.99–1.12) for &varepsilon;3/&varepsilon;4; and 1.12 (95% CrI: 0.94–1.33) for &varepsilon;4/&varepsilon;4 using the &varepsilon;3/&varepsilon;3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10−152), apolipoprotein B (P-trend: 8.7 × 10−06) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10−26) and HDL-C (P-trend: 1.6 × 10−12). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear.Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE &varepsilon;2/&varepsilon;2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined context-dependent associations between variation in risk of ischemic heart disease (IHD) and variation in the 5' promoter region of the apolipoprotein E (APOE) gene among Danish women. The use of a Patient Rule-Induction Method identified elderly women with hypertriglyceridemia with a history of smoking and hypertension. Genetic information including 5' APOE genotypes has been found valuable in predicting IHD.

The apolipoprotein E(APOE) ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism, vascular disease and dementia. The impact of the full range of structural genetic variation in APOE for lipids, lipoproteins and apolipoproteins and for vascular disease in the general population is not known. We systematically sequenced APOE in 10,296 individuals from the Copenhagen City Heart Study and genotyped nine rare variants (frequency≥2/10,296) in 95,227 individuals from the Copenhagen General Population Study. The UK Biobank was used for validation of common APOE variants. Rare mutations in APOE , predicted to be deleterious, are present in 1 in 257 individuals in the general population. In the meta-analysis, multifactorially adjusted hazard ratios (95% confidence intervals) for ϵ44 and ϵ22 versus ϵ33 were 1.15 (1.04–1.26) and 1.02 (0.83–1.24) for ischemic cerebrovascular disease (ICVD), 1.11 (1.04–1.19) and 0.94 (0.83–1.08) for ischemic heart disease (IHD) and 1.03 (0.89–1.17) and 1.49 (1.20–1.87) for peripheral arterial disease (PAD). A multifactorially and ϵ2/ϵ3/ϵ4 adjusted weighted allele score on the continuous scale including all common and rare structural variants showed that for individuals with genetically predicted high plasma apoE and remnant cholesterol the risk for PAD was increased. APOE variants with high apoE, triglycerides, and remnant cholesterol are associated with PAD, whereas common APOE variants with high LDL cholesterol, triglycerides and remnant cholesterol are associated with IHD. APOE variants with low apoE are associated with increased risk of ICVD. These findings highlight that both rare and common structural variations in APOE play a role in vascular disease. [Display omitted] • The APOE ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism. • We sequenced APOE in 10,296 and genotyped rare variants in 95,227 individuals. • ϵ2-like variants are associated with peripheral arterial disease. • Variants with low apoE are associated with ischemic cerebrovascular disease. • Structural variations in APOE beyond the ϵ2 and ϵ4 alleles play a role. [ABSTRACT FROM AUTHOR]

Background and aims Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. Methods We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. Results Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04–1.27) for IHD and 1.16 (1.00–1.36) for MI in men, and 0.94 (0.84–1.05) and 1.04 (0.85–1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03–1.36) for IHD and 1.21 (0.98–1.49) for MI in men, and 0.91 (0.78–1.06) and 0.93 (0.71–1.21) in women. Thus, the present associations were independent of APOE genotype. Conclusion These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations. [ABSTRACT FROM AUTHOR]