The Role of Upregulated APOE in Alzheimer's Disease Etiology.
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ABSTRACT:
SUBMITTER: Gottschalk WK
PROVIDER: S-EPMC4836841 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
Publications
The Role of Upregulated APOE in Alzheimer's Disease Etiology.
Gottschalk William K WK Mihovilovic Mirta M Roses Allen D AD Chiba-Falek Ornit O
Journal of Alzheimer's disease & Parkinsonism 20160209 1
Similar Datasets
Project description:Alzheimer's dis ease (AD) is a leading cause of mortality in the developed world with 70% risk attributable to genetics. The remaining 30% of AD risk is hypothesized to include environmental factors and human lifestyle patterns. Environmental factors possibly include inorganic and organic hazards, exposure to toxic metals (aluminium, copper), pesticides (organochlorine and organophosphate insecticides), industrial chemicals (flame retardants) and air pollutants (particulate matter). Long term exposures to these environmental contaminants together with bioaccumulation over an individual's life-time are speculated to induce neuroinflammation and neuropathology paving the way for developing AD. Epidemiologic associations between environmental contaminant exposures and AD are still limited. However, many in vitro and animal studies have identified toxic effects of environmental contaminants at the cellular level, revealing alterations of pathways and metabolisms associated with AD that warrant further investigations. This review provides an overview of in vitro, animal and epidemiological studies on the etiology of AD, highlighting available data supportive of the long hypothesized link between toxic environmental exposures and development of AD pathology.
| S-EPMC4428475 | biostudies-literature
Project description:Alzheimer's disease (AD) is the leading cause of dementia worldwide. The extracellular deposits of Amyloid beta (A?) in the brain-called amyloid plaques, and neurofibrillary tangles-intracellular tau aggregates, are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, genetic risk factors, and environmental influences. One of the Apolipoprotein E (APOE) alleles-APOE?4, is the major genetic risk factor for late-onset AD (LOAD). APOE is the primary cholesterol carrier in the brain, and plays an essential role in lipid trafficking, cholesterol homeostasis, and synaptic stability. Recent genome-wide association studies (GWAS) have identified other candidate LOAD risk loci, as well. One of those is the triggering receptor expressed on myeloid cells 2 (TREM2), which, in the brain, is expressed primarily by microglia. While the function of TREM2 is not fully understood, it promotes microglia survival, proliferation, and phagocytosis, making it important for cell viability and normal immune functions in the brain. Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner. This review is focusing on the interplay between APOE isoforms and TREM2 in association with AD pathology.
| S-EPMC6337314 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) is the leading cause of dementia, clinically characterized by memory deficits and progressive cognitive decline. Despite decades of research effective therapies are lacking, and a large part of the genetic heritability remains unidentified. ABCA7 and ABCA1, members of the ATP-binding cassette subfamily A (ABCA), were identified as AD risk genes in genome-wide association studies. Nevertheless, genetic and/or functional studies propose a link between AD and two other members of the ABCA subclass, i.e., ABCA2 and ABCA5.Main bodyChanges in expression or dysfunction of these transporters were found to increase amyloid β levels. This might be related to the common role of ABCA transporters in cellular cholesterol homeostasis, for which a prominent role in AD development has been suggested. In this review, we provide a comprehensive overview and discussion on the contribution of the ABCA subfamily to the etiopathogenesis of AD.ConclusionsA better understanding of the function and identification of disease-associated genetic variants in ABCA transporters can contribute to the development of novel therapeutic strategies for AD.
| S-EPMC9044696 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
| S-EPMC9644639 | biostudies-literature
Project description:BackgroundThe Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) tested whether non-steroidal anti-inflammatory drugs (NSAIDs) can prevent Alzheimer's disease (AD). The results were null. We analyzed ADAPT data to examine if the effects of NSAIDs on AD risk differed depending upon APOE genotype or age as has been suggested by previous observational studies.MethodsADAPT randomized 2,528 cognitively intact older adults to either celecoxib, naproxen sodium or placebo; 2,388 participants provided blood samples for APOE genotyping. Proportional hazards regression was used to estimate the effects of naproxen or celecoxib versus placebo on incident AD by age at enrollment and APOE genotype.ResultsThe proportion of subjects providing a biological sample did not differ between the treatment groups. In models of AD risk, none of the tests for 2-way interactions between either NSAID and age or APOE genotype were significant (p > 0.05).ConclusionsThe data did not support the hypothesis that the association between NSAIDs and AD risk differed by age or APOE genotype.
| S-EPMC3435528 | biostudies-literature
Project description:The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared to the common APOE3 allele. Using single-nuclei RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype-dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.
2025-03-17 | GSE237718 | GEO
Project description:BackgroundAPOEɛ4 allele confers greatest genetic risk for Alzheimer's disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk.ObjectiveTo investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer's Disease Neuroimaging Initiative.MethodsParticipants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument.ResultsTotal cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04-7.32), 1.05 for early MCI (1.01-3.22), 1.13 for late MCI (1.05-11.70), 1.21 for AD (1.09-54.05), and 1.13 for composite dementia (MCI or AD; 1.06-11.59) (ps < 0.05, F-statistics > 10).ConclusionHigher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.
| S-EPMC10442640 | biostudies-literature
Project description:Early-onset Alzheimer's disease (EOAD) is generally known as a dominant disease due to highly penetrant pathogenic mutations in the amyloid precursor protein, presenilin 1 and 2. However, they explain only a fraction of EOAD patients (5% to 10%). Furthermore, only 10% to 15% of EOAD families present with clear autosomal dominant inheritance. Studies showed that only 35% to 60% of EOAD patients have at least one affected first-degree relative. Parent-offspring concordance in EOAD was estimated to be <10%, indicating that full penetrant dominant alleles are not the sole players in EOAD. We aim to summarize current knowledge of rare variants underlying familial and seemingly sporadic Alzheimer's disease (AD) patients. Genetic findings indicate that in addition to the amyloid beta pathway, other pathways are of importance in AD pathophysiology. We discuss the difficulties in interpreting the influence of rare variants on disease onset and we underline the value of carefully selected ethnicity-matched cohorts in AD genetic research.
| S-EPMC7896636 | biostudies-literature
Project description:The apolipoprotein E (APOE) and tau proteins play important roles in the pathological development of Alzheimer's disease (AD). Many studies have shown an association between the APOE gene and AD. Association between AD and the newly discovered saitohin (STH) gene, nested within the intron of the tau gene, has been reported. The present study aimed to elucidate the association between APOE and AD, and between STH and AD in our sample.The functional polymorphisms, rs429358 and rs7412, in the APOE gene (which together define the epsilon2, epsilon3, and epsilon4 alleles), and the Q7R SNP in the STH gene, were genotyped in 369 patients with AD and 289 healthy European-Americans. The associations between these two genes and AD were analyzed in a case-control design.Consistent with previously reported results, the frequencies of the APOE epsilon4 allele, epsilon4/epsilon4 genotype and epsilon3/epsilon4 genotype were significantly higher in AD cases than controls; the epsilon4/epsilon4 genotype frequency was significantly higher in early-onset AD (EOAD) than late-onset AD (LOAD); the frequencies of the epsilon2 allele, epsilon3 allele, epsilon3/epsilon3 genotype and epsilon2/epsilon3 genotype were significantly lower in AD cases than controls. Positive likelihood ratios (LRs+) of APOE alleles and genotypes increased in a linear trend with the number of epsilon4 alleles and decreased in a linear trend with the number of epsilon2 or epsilon3 alleles. There was no significant difference in the STH allele and genotype frequency distributions between AD cases and controls.This study confirmed that the epsilon4 allele is a dose-response risk factor for AD and the epsilon4/epsilon4 genotype was associated with a significantly earlier age of onset. Moreover, we found that the epsilon2 allele was a dose-response protective factor for AD and the epsilon3 allele exerted a weaker dose-response protective effect for risk of AD compared with epsilon2. In a clinical setting, APOE genotyping could offer additional biological evidence of whether a subject may develop AD, but it is not robust enough to serve as an independent screening or predictive test in the diagnosis of AD. STH variation was not significantly associated with AD in our sample.
| S-EPMC1526745 | biostudies-literature
Project description:Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid ? (A?) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments.
| S-EPMC7503657 | biostudies-literature