Allele E4 Research Articles

APOE gene polymorphism in ischemic stroke patients from Huizhou and its correlation with blood lipids and homocysteine

ObjectivesTo investigate the correlation between apolipoprotein E (APOE) gene polymorphisms and ischemic stroke and its relationship with blood lipids and homocysteine (HCY) level in Huizhou City. Materials and methodsIn this analytical cross-sectional study, we selected 2612 patients who underwent APOE genotyping from November 2019 to November 2021 at the Third People's Hospital of Huizhou. Among them, 2014 were ischemic stroke patients and 598 were non-stroke patients. The independent variables were ischemic stroke, different genotypes, and different alleles, while the dependent variables were blood lipid levels and HCY levels. ResultsThe distribution frequency of ε4 allele in stroke group was higher than that in non-stroke group (P < 0.05). Compared with ε4 allele carriers in the stroke group, the levels of lipid total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in ε2 and ε3 allele carriers were significantly lower, while the levels of high-density lipoprotein cholesterol (HDL-C) were significantly higher (P < 0.01). The levels of lipid Lipoprotein a (LPa) and small dense low-density lipoprotein (sdLDL) in ε2 allele carriers in stroke group were significantly lower than those of ε4 allele carriers (P < 0.05). Logistics regression analysis showed that age, TC, HCY level and allele ε4 were positively correlated with the risk of ischemic stroke (P < 0.01), TG level was positively correlated with the risk of ischemic stroke in females (P < 0.01). ConclusionsAPOE gene polymorphism is associated with ischemic stroke, and ε4 allele carriers have a higher risk than ε3 allele carriers.

Genes of photoperiod sensitivity and early maturity E1-E4: dynamics of soybean growth in different daylength conditions

Background. Morphometric indicators are crucial for evaluating the development and productivity of soybeans. They are influenced by genetic and environmental factors. The use of nearly isogenic soybean lines is a convenient model for determining the impact of early maturity genes and daylength on growth indicators. The aim of this study was to determine the influence of different daylengths and early maturity genes on soybean morphometric indicators under conditions of the temperate zone (at the latitude of Kharkiv – 50° N). Materials and Methods. The study involved nearly isogenic soybean lines of the “Clark” cultivar with varying sensitivity to daylength. The research covers the results of field experiments over three seasons using different soybean lines. After reaching the V3 stage, some plants were subjected to short-day conditions for 14 days. Morphological indicators of ten plants per experimental variant were determined: plant height, dry weight, leaf number, and leaf surface area of soybean plants. Morphometric measurements were taken on the day of the beginning of different daylength treatments and on days 7, 14 and 21. The study results are presented as the mean values of the investigated parameters (plant height, dry weight, number of leaves and leaf surface area of soybean plants). Results. It was shown that under long-day conditions, dominant alleles of the E1 and E3 genes increased the dry weight of plants, while the dominant allele E2 increased plant height. The dominant allele E4 had no significant effect on plant height and weight indicators of soybean plants. Plants with dominant alleles of genes E1-E4 under long-day conditions had smaller leaf area compared to lines with recessive alleles of these genes. Conclusions. The obtained results on the relationships between genetic and environmental factors in influencing soybean plant height, weight, and leaf area can be useful in improving soybean yield and selecting cultivars that will be productive in high latitude conditions.

Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor.

Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

A Simplified Proteomics LC-MRM-MS Assay for Determination of apoE Genotypes in Plasma Samples.

Apolipoprotein E (apoE), a polymorphic plasma protein, plays a pivotal role in lipid transportation. The human apoE gene possesses three major alleles (ε2, ε3, and ε4), which differ by single amino acid (cysteine to arginine) substitutions. The ε4 allele represents the primary genetic risk factor for Alzheimer's disease (AD), whereas the ε2 allele protects against the disease. Knowledge of a patient's apoE genotype has high diagnostic value. A recent study has introduced an LC-MRM-MS-based proteomic approach for apoE isoform genotyping using stable isotope-labeled peptide internal standards (SIS). Here, our goal was to develop a simplified LC-MRM-MS assay for identifying apoE genotypes in plasma samples, eliminating the need for the use of SIS peptides. To determine the apoE genotypes, we monitored the chromatographic peak area ratios of isoform-specific peptides relative to a peptide that is common to all apoE isoforms. The assay results correlated well with the standard TaqMan allelic discrimination assay, and we observed a concordance between the two methods for all but three out of 172 samples. DNA sequencing of these three samples has confirmed that the results of the LC-MRM-MS method were correct. Thus, our simplified UPLC-MRM-MS assay is a feasible and reliable method for identifying apoE genotypes without using SIS internal standard peptides. The approach can be seamlessly incorporated into existing quantitative proteomics assays and kits, providing additional valuable apoE genotype information. The principle of using signal ratios of the protein isoform-specific peptides to the peptide common for all of the protein isoforms has the potential to be used for protein isoform determination in general.

The Role of Apolipoprotein E4 Allele in the Gut Microbiome of Puerto Ricans with Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) causes dementia, a debilitating disorder that gradually declines mental function and ends with death. Evidence suggests that the apolipoprotein E (ApoE) gene influences Alzheimer’s risk. Allele E2 is neuroprotective, E3 is neutral, and E4 is associated with a higher genetic risk for AD. Our main goal was to study the gut microbiome of Puerto Ricans with AD compared to unimpaired cognitive controls and its association with ApoE allele variants. We hypothesized that people with AD and does with less protective alleles have reduced microbial diversity.MethodsWe present the preliminary results of forty eight participants (n = 48), 24 with AD and 24 controls, with clinical and cognitive assessments. Fecal samples were collected for genomic DNA extractions followed by 16S rRNA genes (V4 region) amplification and ApoE genotyping was done at the PR‐INBRE CRI genomics core, using real‐time PCR TaqMan‐BHQ probes.ResultsControls, even with a single E4 allele, showed higher abundance of Ruminococcus bicirculans, absent in AD patients. Clostridium leptum was in higher abundance in controls with neuroprotective alleles E2E3 and in considerably reduced abundance in AD patient with E3E4 phenotype. Methanobrevibacter was in higher abundance in participants with any E4 allele than those with either E2 or E3 alleles. Faecalibacterium and Bacteroides were in higher abundance in controls compared to AD patients. Faecalibacterium, Ruminococcus, Clostridium and Bacteroides are anti‐inflammatory taxa and butyrate producers. Methanobrevibacter could favor metabolizing acetate to methane and thus antagonize the health‐directed butyrate benefits.ConclusionParticipants with any ApoE E4 allele have decreasing butyrate‐producing gut bacteria. This developing study area may open the possibility for preventive microbiome‐based therapies that could result in a clinical benefit for patients with and without AD.

Amyloidosis at Putamen Predicts Vulnerability to Alzheimer’s Disease

AbstractBackgroundUsing merely cortical amyloid burden in a binary approach was commonly adopted for determining if an individual is under AD pathology in both clinical trials and basic research. Subcortical amyloid, compared to cortical amyloid, showed a larger inter‐subject heterogeneity, which may provide valuable insights to their vulnerability to Alzheimer’s disease beyond cortical amyloid.MethodA total of 1344 individuals from ADNI database had 18F‐AV45 amyloid PET scans available. Regional AV45 signal was computed by averaging the signal from gray matter voxels in each region and then normalized to the mean signal in the composite reference region [1, 2]. The cortical AV45 was averaged over extensive regions consisting of frontal, anterior/posterior cingulate, lateral parietal, and lateral temporal regions. The AV45 signal in the subcortex, including putamen and caudate, were also computed. Only the participants under AD pathology, determined based on cortical amyloid positivity, were included in the analysis. The association analysis between subcortical AV45 and cognition was conducted before and after adjusting cortical AV45. A linear fitting of cortical AV45 and AV45 at putamen was conducted and participants were categorized into high (HighP), middle (MidP) and low (LowP) putamen amyloid group thresholded with ±0.5 standardized residuals. Statistical analysis was carried out to evaluate the difference of clinical diagnosis, hippocampal volume and APOE ε4 genotype. The relevance of amyloid at putamen with the rate of cognitive decline was examined.ResultPutamen, compared to caudate, had a stronger association with ADAS‐cog13 and MoCA, such an association remained exist after adjusting cortical AV45. Despite distinct AV45 at putamen, participants in LowP, MidP and HighP groups had no cortical AV45 difference. The AV45 at putamen was significantly higher in individuals with more ε4 alleles (ε4 homozygous &gt; ε4 heterozygous &gt; non‐ ε4) and more advance clinical stages (Dementia &gt; MCI &gt; CN). The individuals with higher AV45 at putamen had smaller hippocampal volume and faster cognitive decline.ConclusionOur finding suggested that amyloidosis at putamen is a valuable imaging marker beyond cortical amyloid in predicting if a participant is more vulnerable to Alzheimer’s dementia.

Amyloidosis at Putamen Predicts Vulnerability to Alzheimer’s Disease

AbstractBackgroundUsing merely cortical amyloid burden in a binary approach was commonly adopted for determining if an individual is under AD pathology in both clinical trials and basic research. Subcortical amyloid, compared to cortical amyloid, showed a larger inter‐subject heterogeneity, which may provide valuable insights to their vulnerability to Alzheimer’s disease beyond cortical amyloid.MethodA total of 1344 individuals from ADNI database had 18F‐AV45 amyloid PET scans available. Regional AV45 signal was computed by averaging the signal from gray matter voxels in each region and then normalized to the mean signal in the composite reference region [1, 2]. The cortical AV45 was averaged over extensive regions consisting of frontal, anterior/posterior cingulate, lateral parietal, and lateral temporal regions. The AV45 signal in the subcortex, including putamen and caudate, were also computed. Only the participants under AD pathology, determined based on cortical amyloid positivity, were included in the analysis. The association analysis between subcortical AV45 and cognition was conducted before and after adjusting cortical AV45. A linear fitting of cortical AV45 and AV45 at putamen was conducted and participants were categorized into high (HighP), middle (MidP) and low (LowP) putamen amyloid group thresholded with ±0.5 standardized residuals. Statistical analysis was carried out to evaluate the difference of clinical diagnosis, hippocampal volume and APOE e4 genotype. The relevance of amyloid at putamen with the rate of cognitive decline was examined.ResultPutamen, compared to caudate, had a stronger association with ADAS‐cog13 and MoCA, such an association remained exist after adjusting cortical AV45. Despite distinct AV45 at putamen, participants in LowP, MidP and HighP groups had no cortical AV45 difference. The AV45 at putamen was significantly higher in individuals with more e4 alleles (e4 homozygous &gt; e4 heterozygous &gt; non‐ e4) and more advance clinical stages (Dementia &gt; MCI &gt; CN). The individuals with higher AV45 at putamen had smaller hippocampal volume and faster cognitive decline.ConclusionOur finding suggested that amyloidosis at putamen is a valuable imaging marker beyond cortical amyloid in predicting if a participant is more vulnerable to Alzheimer’s dementia.

4 Impact of APOE-ε Alleles on Brain Structure and Function in Healthy Older Adults: A VBM and DTI Replication Study

Objective:The Apolipoprotein E (APOE) gene has been established in the Alzheimer’s disease (AD) literature to impact brain structure and function and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and neuropsychological measures present as useful, non-invasive tools to investigate the impact of APOE-e allele status on grey matter structure, white matter integrity, and cognitive functioning, respectively. Nonetheless, studies to date have revealed mix findings and few studies have taken a multimodal approach to investigating APOE’s effects. Thus, the objective of the current study was to replicate and expand upon the multimodal neuroimaging study conducted by Honea et al. (2009), that examined the impact of APOE-e4 presence on brain structure and cognitive function in healthy older adults, with the addition of APOE-e2 carriers and cognitive composite measures. The aim of the current replication study was to identify reliable changes to grey matter volume and white matter integrity in healthy older adults as it relates to APOE-e allele presence and cognitive performance. This represents one of the first studies to investigate both the risk and protective effects of APOE-e alleles (e4 and e2 respectively) on measures of cognitive performance, GMV and white matter integrity in healthy older adults.Participants and Methods:Data were obtained from the Alzheimer’s Disease Initiative phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-e2+ N= 17, APOE-e3e3 N= 64, APOE-e4+ N=35). Voxel-based morphometry (VBM) and tract based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity respectively between APOE-e2+ and APOE-e3e3 controls, and again between APOE-e4+ and APOE-e3e3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with covariates of age, sex, education, and cognitive scores were correlated with imaging metrics within groups (Pearson r) to examine associations between cognitive performance and brain structure.Results:Consistent with findings from Honea et al. (2009), no significant differences were seen across APOE groups, within-groups in MRI metrics, or cognitive performance (p&gt;0.05, corrected for multiple comparisons). Taking a similar approach to Honea and company, nonsignificant, trend-level results were examined (p&lt;0.2, corrected for multiple comparisons) and suggested: 1) Decreased GMV and increased mean diffusivity (MD) were present in APOE-e4+ compared to APOE-e3e3 and 2) Increased GMV and fractional anisotropy (FA) were present in APOE-e2+ compared to APOE-e3e3.Conclusions:The current study replicated and extended previous findings. Trend-level findings across both the current and replicated study suggests there may be subtle neurostructural differences in healthy aging as a function of APOE-e4 status. The current study additionally found potential subtle differences in GMV and white matter integrity in APOE-e2 carriers at the trend-level, consistent with previous reports of APOE-e2 's protective effects against neurodegeneration. Although these findings should be interpreted with caution, trend-level effects seen in the current study are consistent with previous research and may hold important implications for APOE neuromechanisms.

Alzheimer's Disease and Suicide: An Integrative Literature Review.

Suicide has been described in patients with Alzheimer's disease. Some promising medications for treating Alzheimer's disease have had their studies suspended because they increase the risk of suicide. Understanding the correlations between suicide and Alzheimer's disease is essential in an aging world. A search was carried out on electronic websites (PubMed and Scielo) using the MeSH Terms "suicide" and "Alzheimer" (1986-2023). Of a total of 115 articles, 26 were included in this review. Depression and the allele ε4 of Apolipoprotein (APOE4) were demonstrated to be the main risk factors for suicide in patients with Alzheimer's disease. Adequately delineating which elderly people are vulnerable to suicide is important so that new treatments for Alzheimer's disease can be successful. This review showed a need for new studies to investigate the interface between Alzheimer's disease and suicide.

Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.

Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.

Apolipoprotein E ε2 allele is associated with lower risk of carotid artery obstruction in a population-based autopsy study

IntroductionApolipoprotein E (APOE) ε4 allele has been associated with higher carotid atherosclerosis risk, while the APOE-ε2 seems to decrease this risk. Data from autopsy studies, where carotid arteries can be evaluated in their full extension, is scarce. Therefore, we investigated the association between APOE alleles and direct morphometric measurements of carotid atherosclerosis in an autopsy study with an admixed sample. MethodsWe measured the intima-media thickness (IMT) and stenosis of the common (CCA) and internal carotid (ICA) arteries. The APOE polymorphisms were determined by real-time polymerase chain reaction. Participants were classified into three groups according to the APOE alleles (ε2, ε3, and ε4). We evaluated the association between APOE groups and carotid atherosclerosis using adjusted regression models and included interaction terms of APOE alleles with age, sex, and race. ResultsWe evaluated 1,850 carotid artery samples from 185 participants (mean age=75±12 years old, 55% female, and 71% White). The APOE-ε2 group (n=17) had a lower carotid obstruction and a lower number of severe stenoses (≥ 70%). Having at least one ε4 allele (n=51) was not associated with carotid atherosclerosis. APOE alleles were also not associated with carotid IMT. Age, sex, and race did not modify these relationships. ConclusionAPOE-ε2 carriers had a lower percentage of carotid obstruction and less severe stenosis. APOE-ε4 was not related to a higher risk of carotid atherosclerosis in this cross-sectional population-based autopsy study.

APOE ε4 allele, along with G206D-PSEN1 mutation, alters mitochondrial networks and their degradation in Alzheimer's disease.

Alzheimer's disease remains the most common neurodegenerative disorder, depicted mainly by memory loss and the presence in the brain of senile plaques and neurofibrillary tangles. This disease is related to several cellular alterations like the loss of synapses, neuronal death, disruption of lipid homeostasis, mitochondrial fragmentation, or raised oxidative stress. Notably, changes in the autophagic pathway have turned out to be a key factor in the early development of the disease. The aim of this research is to determine the impact of the APOE allele ε4 and G206D-PSEN1 on the underlying mechanisms of Alzheimer's disease. Fibroblasts from Alzheimer's patients with APOE 3/4 + G206D-PSEN1 mutation and homozygous APOE ε4 were used to study the effects of APOE polymorphism and PSEN1 mutation on the autophagy pathway, mitochondrial network fragmentation, superoxide anion levels, lysosome clustering, and p62/SQSTM1 levels. We observed that the APOE allele ε4 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62/SQSTM1, probably due to an inefficient autophagy. Moreover, G206D-PSEN1 mutation causes an impairment of the integrity of mitochondrial networks, triggering high superoxide anion levels and thus making APOE 3/4 + PSEN1 fibroblasts more vulnerable to cell death induced by oxidative stress. Of note, PSEN1 mutation induces accumulation and clustering of lysosomes that, along with an increase of global p62/SQSTM1, could compromise lysosomal function and, ultimately, its degradation. The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer's disease. Further research in this area may help to develop targeted therapies for the treatment of Alzheimer's disease.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid β (Aβ42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aβ hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aβ and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aβ deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

Alzheimer’s disease risk alleles of PICALM gene may accelerate cognitive (memory and attention) performance in middle‐aged healthy APOE‐ε4 carriers

AbstractBackgroundThe APOE (allele ε4) and PICALM (SNPs rs541458: allele T; and rs3851179: allele G) genes were recognized as risk factors for late‐onset Alzheimer’s disease (AD). However, effects of these risk genes on the cognitive functions of healthy individuals are still not determined and their possible interactions have never been studied. We investigated the preclinical influence of both genes on brain cognitive functions in a healthy middle‐aged population.MethodSeventy three healthy adults (50‐63 y/o) completed computer tasks measuring attention, cognitive control and memory. MSIT task included an easy‐control condition and an attentionally demanding condition with combined cognitive conflicts. Sternberg’s task included an easy condition (there is a need to memorize 4 letters strings) and a hard‐one (with 8 letters strings). APOE (rs429358/rs7412) and PICALM (rs3851179 and rs541458) alleles were determined using a traditional Sanger sequencing protocol. The data was divided according to the genetic tests results (control group: absence of ε4 and less‐risky PICALM alleles; the double risk group: ε4‐carriers, and homozygous carriers of high‐risk PICALM alleles; single risk group: ε4‐carriers and less‐risky PICALM alleles). ANOVA was used to determine the effects of genetic variants on task performance (reaction time (RT) and accuracy for easy/hard MSIT and Sternberg conditions).ResultResults revealed that while the groups did not differ in accuracy or RTs for easy conditions, they did differ significantly on hard conditions (p&lt;0.05). The single‐risk group showed longer RTs than the control group in both tasks. The effect was preserved when performing the analysis of covariance (ANCOVA) with the age as a covariate.ConclusionAD risk genes, APOE and PICALM, can affect cognitive abilities even in healthy individuals. APOE‐ε4‐carriers needed longer time to process difficult stimuli but surprisingly an addition of PICALM risk alleles seemed to reverse this tendency. Further studies are needed to unambiguously determine the effects of the PICALM and its interactions with other risk genes (including APOE) in modulating the cognitive abilities of still healthy individuals.[Supported by National Science Centre, Poland, no. 2018/31/N/HS6/03551.]

Impact of APOE on amyloid progression in Alzheimer disease

AbstractBackgroundIt is well recognized that β‐amyloid (Aβ) pathology plays an important role in Alzheimer Disease (AD) pathophysiology. The amount of Aβ in the brain varies substantially within both preclinical and symptomatic AD populations. Part of this inter‐individual variability in amyloid pathology may be explained by the genotype variation of Apolipoprotein E (APOE), with the allele e4 found to be the most significant genetic risk factor for late‐onset AD. However, the impact of APOE genotype on the rate of amyloid accumulation is less clear and requires further investigation. In this study, we focus on longitudinal approaches to investigate how APOE genotype influences the trajectories of the Aβ pathology.MethodFor this project, we used longitudinal data of participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Washington University Knight Alzheimer Disease Research Center (Knight ADRC). We included 247 participants with available APOE genotype data, and longitudinal measure of Aβ burden via florbetapir (AV45) PET data, see table 1. Imaging PET data from ADNI and ADRC were harmonized using a centiloid conversion. The rate of Aβ accumulation was estimated as the slope of the random coefficient model using all available time points of longitudinal imaging data for each participant, controlling for age, sex, education and cohort. Generalized linear model was used to test the association between APOE genotype and the rate of change in amyloid.ResultThe rate of change in amyloid burden was not significantly different among all APOE genotype groups (Figure 1A; F = 1.64, p = 0.15). When looking specifically at the effect of allele count for APOE‐e4, we observed the rate of change in amyloid burden increased with e4 allele (Figure 1B; F = 4.18, P = 0.02). Pairwise comparison showed significant differences in rate of amyloid accumulation between e4e4 and e2e3 APOE genotype groups (p = 0.04), and between e4e4 and e3e3 APOE genotype groups (p = 0.04), see table 2. There was no significant difference in rate of amyloid accumulation between other genotype groups.ConclusionAPOE e4 increases AD risk by accelerating the amyloid deposition. Future direction will include a larger sample size to investigate the effect of e2 and e3 on amyloid progression in AD.

Apolipoprotein E polymorphism in a Romanian population

Abstract Background: Apolipoprotein E (ApoE) is a ubiquitous protein involved in maintaining cholesterol homeostasis and lipoprotein clearance from circulation. It is coded by three alleles (ε2, ε3, ε4) with six genotypes (ε3/ε3, ε3/ε4, ε2/ε3, ε4/ε4, ε2/ε4, and ε2/ε2). Several studies have shown a relationship between ApoE-specific isoforms and different diseases. There are few data about the prevalence of ApoE polymorphism in the Romanian population. We aimed to assess the prevalence of Apolipoprotein E alleles in a healthy population from Romania and compare it with the data found in other countries of Europe. Methods: ApoE genotype was examined in 187 unrelated healthy volunteers (131 males and 56 females) from the region of southwest Romania (mean age 48.04 ± 8.35 years). Analysis of ApoE genotype variants was done using the PCR method with allele-specific oligonucleotide primers. Results: The frequency of heterozygote genotypes ε2/ε3, ε2/ε4, and ε3/ε4 was 4.8%, 1.6%, and 24.73%, respectively, while the frequency of homozygote genotypes ε2/ε2, ε3/ε3, ε4/ε4 was 0.5%, 66.12%, and 2.1%, respectively, with a mean frequency of ε2, ε3 and ε4 alleles of 6.9%, 96.25%, and 28.49%, respectively. East European countries have the lowest mean frequency of the ε4 allele (9.96%), and the highest frequency of the ε4 allele (23.38%) is in the Nordic Countries. Conclusions: The ε4 allele prevalence in this Romanian population is higher in comparison with other European countries, similar to Nordic countries of Europe.

Apolipoprotein E Gene Polymorphism, Serum Lipids, and Risk of Superficial Fungal Infections in Egyptian Patients - A Preliminary Case-Controlled Study.

Apolipoprotein E (APOE) gene isoforms have been found to affect the risk of superficial fungal infections (SFIs). However, the data only cover a few ethnicities. The present work intended to investigate the association of APOE gene polymorphism and serum lipids with the susceptibility of SFIs among a group of Egyptian patients. Standard laboratory methods were used to estimate the serum lipid profile, and polymerase chain reaction-restriction fragment length polymorphism was used to detect APOE gene polymorphism in deoxyribonucleic acid extracted from 150 SFI patients and an equal number of apparently healthy matched controls. Serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol were significantly higher in the studied patients than in controls. The APOE gene ε2, ε4 alleles, and ε3/4 and ε3/2 genotypes were significantly distributed in the patients than in the controls. APOE ε3/3 genotype was predominant in dermatophytosis and tinea versicolour patients, and ε3/4 genotype was predominant in candidiasis. ApoE alleles ε2 and ε4, and genotypes ε2/3 and ε3/4 are linked to SFI and may be risk factors, whereas allele ε3 and genotype ε3/3 may be protective for SFI in the Egyptian population studied. The lipid profile results suggest that hyperlipidemia may provide evidence for SFI pathogenesis. However; further large-scale studies are still needed to validate our results.

Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline

AbstractBackgroundThe APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults.MethodWe used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time.ResultWe included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3).ConclusionAmong cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.

Apolipoprotein E genotypes were not associated with intracranial atherosclerosis: a population-based autopsy study

Apolipoprotein E gene (APOE) ε4 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study. We measured the stenosis in the 12 arteries of the Circle of Willis using postmortem morphometric measurements. The APOE polymorphism was determined by real-time polymerase chain reaction. We assessed the association between APOE polymorphism and IAD using regression models adjusted for sociodemographic and clinical variables. We also verified the modifier effect of age, sex, and race on this association. We stratified the analysis by age group to investigate the possibility of attrition bias. In 400 participants (mean age=73.2±12.3 years old, 51% female, and 64% White), IAD was evaluated in 4,504 artery segments. APOE-ε4 was not associated with IAD nor with the number of artery stenosis compared to non-APOE-ε4 carriers. Sociodemographic variables did not modify this relationship. Among participants older than 70 years, there was a trend towards an association between APOE allele ε4 and a lower stenosis index in the middle cerebral artery, suggesting attrition bias related to the APOE-ε4 effect on mortality. APOE alleles were not associated with IAD in this population-based autopsy study. Lower stenosis in older participants suggests the possibility of attrition bias.

Correlation of ApoE Gene Polymorphism with Coronary Heart Disease Severity in Patients with Acute Coronary Syndrome Who Receive Statin Therapy, Padang, Indonesia

Coronary Heart Disease (CHD) is still the most common cause of death. Ischemic heart disease causes more than 7 million (12.8%) deaths worldwide. It is estimated that 3,750,000 Indonesians have CHD. CHD is a disease with many risk factors. ApoE gene polymorphism is associated with atherosclerosis and plays a role in lipid metabolism, which is 2-16% affecting variability in LDL levels. This study aims to look at the relationship between ApoE gene polymorphism and the severity of coronary heart disease. Data regarding ApoE gene polymorphism was obtained using polymerase chain reaction (PCR). DNA was isolated from white blood cells using DNA purification kit. ApoE2, ApoE3, ApoE4 alleles were detected by DNA sequencing. Data on the severity of coronary heart disease were obtained from angiography and were calculated based on SYNTAX scores. In this study, ApoE was obtained with e2 allele frequencies (4.63%), e3 (78.70%), and e4 (16.67%) with E2 / 2 (0%), E2 / 3 (3.70%), E2 / 4 (5.56%), E3 / 3 (64.81%), E3 / 4 (24.07%), and E4 / 4 (1.85%). The relationship between the SYNTAX score and the ApoE genotype has no significant difference. ApoE3 / 4 genotype has the highest SYNTAX score and the e4 allele has the most influence on CHD despite the influence of statin therapy.