APOE genotypes, lipid profiles and associated clinical markers in a Finnish population with cardiovascular disease risk factors

Introduction: APOE ɛ4 allele predisposes to high cholesterol and increases the risk for lifestyle-related diseases such as Alzheimer’s disease (AD) and cardiovascular diseases (CVD). The aim of this study was to analyse interrelationships of APOE genotypes with lipid metabolism and lifestyle factors in middle-aged Finns among whom the CVD risk factors are common. Methods: Participants (n=211) were analysed for APOE ε genotypes, physiological parameters and health- and diet-related plasma markers. Lifestyle choices were determined by a questionnaire. Results: APOE genotypes ε3/ε4 and ε4/ε4 (ε4 group) represented 34.1% of the participants. Genotype ε3/ε3 (ε3 group) frequency was 54.5%. Carriers of ε2 (ε2 group; ε2/ε2, ε2/ε3 and ε2/ε4) represented 11.4%; 1.9 % were of the genotype ε2/ε4. The LDL and total cholesterol levels were lower (P<0.05) in the ε2 carriers than in the ε3 or ε4 groups, while the ε3 and ε4 groups did not differ. Proportions of plasma saturated fatty acids were higher (P<0.01) and omega-6 fatty acids lower (P=0.01) in the ε2 carriers compared with the ε4 group. The ε2 carriers had a higher (P<0.05) percentage of 22:4n-6 and 22:5n-6 and a lower (P<0.05) percentage of 24:5n-3 and 24:6n-3 than individuals without the ε2 allele. Conclusions: The plasma fatty acid profiles in the ε2 group were characterised by higher SFA and lower omega-6 fatty acid proportions. Their lower cholesterol values indicated a lower risk for CVD compared with the ε4 group. A novel finding was that the ε2 carriers had different proportions of 22:4n-6, 22:5n-6, 24:5n-3 and 24:6n-3 than individuals without the ε2 allele. The significance of the differences in fatty acid composition remains to be studied.

APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population

Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene’s associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer’s Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10−4) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings.

Relationship between Urinary AD7c-NTP with Cerebral Microbleeds Based on APOE Genotype

Objective. This study was performed to investigate the association between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) with cerebral microbleeds (CMBs) based on the apolipoprotein E (APOE) genotypes. Methods. A total of 471 patients with acute cerebral infarction screened by magnetic sensitive imaging were enrolled in this study. Among them, twenty-seven cases of mixed CMBs were excluded. A total of 444 patients were divided into two groups according to the presence or absence of CMBs: CMBs group ( n = 92 ) and noncerebral microbleeds group (nCMBs) ( n = 352 ). Urine AD7c-NTP levels were measured using a human enzyme immunoassay kit. Results. In patients with lobar CMBs, there was an interaction between urine AD7c-NTP levels and APOE genotypes ( p = 0.01 ). In patients with APOE ε3/ε3 allele, the odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 0.92 (95% CI: 0.70-1.19). In patients with APOE ε2+ or ε4+ allele, the multivariate-corrected odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 2.95 (95% CI: 1.38-6.27). Conclusion. A higher level of urinary AD7c-NTP is involved in lobar CMBs, not deep CMBs.

Association of ApoE Genotypes and Recovery From Intracerebral Hemorrhage in Very Low Birth Weight Infants

Background and Purpose: Associations of APOE genotypes with intracerebral hemorrhage (ICH) in preterm infants were previously described. In adults, APOE-ε4 genotype has been proposed as susceptibility factor for impaired recovery after cerebral insult. We here aim to determine APOE genotype-specific neurological consequences of neonatal ICH at school age. Methods: In this multicenter observational cohort study, very low birth weight (<1500 g, <32 weeks gestational age) children were studied for cerebral palsy (CP) after ultrasound diagnosed ICH stratified by APOE genotype. Follow-up examination was done at the age of 5 to 6 years. Study personnel were blinded for perinatal information and complications. Participants were born between January 1, 2009 and December 31, 2013 and enrolled in the German Neonatal Network. Of 8022 infants primarily enrolled, 2467 children were invited for follow-up between January 1, 2014 and December 31, 2019. Univariate analyses and multivariate logistic regression models were used to assess the impact of APOE genotype (APOE-ε2, APOE-ε3, APOE-ε4) on CP after ICH. Results: Two thousand two hundred fifteen children participated at follow-up, including 363 children with ultrasound diagnosed neonatal ICH. In univariate analyses of children with a history of ICH, APOE-ε3 carriers had lower frequencies of CP (n=33/250; 13.2 [95% CI, 9.4%–17.8%]), as compared to APOE-ε2 (n=15/63; 23.8 [14.6%–35.3%], P =0.037) and –ε4 carriers (n=31/107; 29.0 [21.0%–38.0%], P <0.001), respectively. Regression models revealed an association of APOE-ε4 genotype and CP development (odds ratio, 2.77 [1.44–5.32], P =0.002) after ICH. Notably, at low-grade ICH (grade I) APOE-ε4 expression resulted in an increased rate of CP (n=6/39; 15.4 [6.7–29.0]) in comparison to APOE-ε3 (n=2/105; 1.9 [0.4%–6.0%], P =0.002). Conclusions: APOE-ε4 carriers have an increased risk for long-term motor deficits after ICH. We assume an effect even after low-grade neonatal ICH, but more data are needed to clarify this issue.

801Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK biobank

Background The APOE gene has three main alleles; APOE-E2, E3 and E4 (global frequencies: 8%, 78%, 14%) carrying differential risk for conditions such as dementia and cardiovascular disease. Due to the clinical significance of variation at this locus, we explored disease associations of APOE genotypes using a hypothesis-free, phenome-wide association study (PheWAS) approach. Methods Utilising medical and genetic data available from the UK Biobank for 337,484 white British participants aged 37–73 years, we screened for associations between APOE genotypes (E4E4, E3E4, E2E4, E2E3 and E2E2) and ≥825 disease outcomes, using E3E3 as a reference. Results Case-control PheWAS analyses revealed associations with 37 disease outcomes from 17 distinct conditions after multiple test correction. As expected, E4E4 and E3E4 associated with risk of Alzheimer’s disease (p &lt; 10-46 for both), hypercholesterolemia (p &lt; 10-17), and cardiovascular diseases (p &lt; 10-4). Novel findings included E4-associated increased risk of chondrocalcinosis (E4E4), and protection against obesity (E4E4), type 2 diabetes (E4E4, E4E3), and chronic airway obstruction (E4E4; all p ≤ 3.2 × 10-4). Notably, E2E2 homozygosity augmented risks of peripheral vascular diseases, and cervical disorders (p ≤ 1·9 × 10-5). Conclusions PheWAS assessment of APOE-associated risk for a wide spectrum of diseases amongst this large, white British population, detected well-established, and novel APOE-disease associations warranting further validation. Key messages While APOE-E4 is risky for Alzheimer’s, and cardiovascular diseases, it may be protective against some metabolic conditions. While the E2 allele is often considered beneficial, homozygosity-associated risks may contribute to its relatively low prevalence.

APOE E2/E2 Is Associated with Slower Rate of Cognitive Decline with Age

Background: The E4 allele of the APOE gene is known to be associated with cognitive impairment. However, a limited number of studies have examined the association between the E2 allele and longitudinal changes of cognitive function. Objective: To determine whether rates of cognitive change differ in carriers of the APOE E2 allele compared to other genotypes. Methods: We conducted a secondary analysis of data from two ongoing longitudinal cohort studies, the Long Life Family Study (LLFS) and New England Centenarian Study (NECS). We included participants who had APOE genotyping data, data from longitudinal administrations of the Telephone Interview for Cognitive Status (TICS), and age, sex, and education available. We assessed whether cognitive change as measured by rate of decline in TICS score differed among people with different APOE genotypes. We used a hierarchical mixed effect model with APOE genotypes, their interactions with age, and potential confounders. Results: After adjusting for sex and education, in carriers of the common E3/E3 genotype, TICS score decreased by 0.15 points per year of age. In those with the E2/E2 genotype, TICS score decreased by 0.05 points per year of age, a significantly slower rate of decline (p = 0.017). We observed no protective effect of the E2/E3 genotype on cognitive decline. Conclusion: These results suggest a protective effect of the E2/E2 genotype on a measure of global cognitive function.

Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ɛ4 was a risk factor for AD, whereas APOE ɛ2 protected against it. The effects of APOE ɛ4 and ɛ2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ɛ4/ɛ4 and lower frequency of APOE ɛ3/ɛ3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

Association of APOE polymorphisms with lipid-lowering efficacy of statins in atherosclerotic cardiovascular diseases

Introduction: Apolipoprotein E (APOE) gene is a promising candidate for the diagnosis of hyperlipoproteinaemia and atherosclerosis. Polymorphisms in APOE have been reported to result in differential efficacies of statins in atherosclerotic cardiovascular diseases. Method: We classified APOE genotypes of 225 patients treated with atorvastatin and analysed the relationship between genotypes and blood lipid levels. Results: The baseline levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lower in APOE ε4 than APOE ε3 carriers. Levels of TC and LDL-C decreased significantly after 1 month of atorvastatin treatment. Statins have a higher significant effect in reducing TC and LDL-C levels in APOE ε4 genotype. Conclusion: Polymorphism in APOE is related to the efficacy of atorvastatin in reducing the levels of TC and LDL-C. Keywords: Apolipoprotein E, lipid-lowering efficacy, polymorphism, statin, total cholesterol