Abstract:Apolipoprotein E (ApoE) plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system (CNS). In humans, ApoE exists in three different isoforms: ε2, ε3 and ε4. ApoE ε3 is the most common isoform, while the ε4 isoform confers the greatest genetic risk for Alzheimer's disease (AD). However, the mechanisms underlying how ApoE contributes to the pathogenesis of AD are still debated. ApoE has been shown to impact amyloid β (Aβ) deposition and clearance in the brain. … Show more
“…A few proteins have also been identified as amyloid‐interfering molecules which can affect fibril assembly, examples of such proteins are transthyretin , proteins containing a BRICHOS domain , clusterin , and apolipoprotein E (ApoE) . In this context, the 34 kDa plasma protein ApoE is of specific interest due to its strong clinical impact on the development of AD . ApoE is a lipid‐binding protein involved in cholesterol metabolism.…”
Alzheimer’s disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid‐binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose‐dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation‐dependent mechanism where free monomers are added onto a nucleus in a template‐dependent manner. Using a combination of surface plasmon resonance and thioflavin‐T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.
“…A few proteins have also been identified as amyloid‐interfering molecules which can affect fibril assembly, examples of such proteins are transthyretin , proteins containing a BRICHOS domain , clusterin , and apolipoprotein E (ApoE) . In this context, the 34 kDa plasma protein ApoE is of specific interest due to its strong clinical impact on the development of AD . ApoE is a lipid‐binding protein involved in cholesterol metabolism.…”
Alzheimer’s disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid‐binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose‐dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation‐dependent mechanism where free monomers are added onto a nucleus in a template‐dependent manner. Using a combination of surface plasmon resonance and thioflavin‐T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.
“…Certainly, because vitamin E and cholesterol share mechanisms of delivery to cells via LDL particles, vitamin E‐APOE genotype interactions could involve these common uptake pathways. However, another hypothesis, not linked to vitamin E, is that APOE binds and clears amyloid β, the toxic peptide central to AD pathogenesis [17,20]. A biological explanation of the genotype‐treatment interaction demonstrated here awaits further work on the role of APOE in AD pathogenesis.…”
Section: Discussionmentioning
confidence: 80%
“…However, APOE has been shown to have the largest effect size of any AD genetic risk factor. The APOE ε4 allele increases the risk of AD by two‐fold to three‐fold in heterozygous ε4 carriers and 12‐fold in homozygous ε4 [17]. For other AD genetic risk variants, odds ratios are less than 3.0 with most between 1.1 and 1.4 [18].…”
IntroductionBecause apolipoprotein E (APOE) genotypes are known risk factors for Alzheimer's disease (AD), they have been measured in clinical trial participants to determine their effect on treatment outcome.MethodsWe determined APOE genotypes in a subset of subjects (N = 415) who participated in a randomized controlled trial of vitamin E and memantine in 613 veterans with mild-to-moderate AD.ResultsSimilar to the primary study, substudy participants receiving vitamin E also had slower functional decline than those receiving placebo. Overall, there was no difference in the rate of functional decline between APOE ε4 allele carriers and noncarriers. A significant interaction was observed between treatment and the APOE genotype on AD progression: ε4 carriers declined faster than noncarriers in the vitamin E plus memantine treatment arm.DiscussionAPOE genotypes may modulate AD treatment response and should be included in the design of future randomized controlled trials.
“…The protein APOE is involved in cholesterol metabolism and lipid homeostasis in the brain 23 . APOE has three alleles e2, e3 and e4 and carriage of APOE-e4 is the largest known genetic risk factor of LOAD with e4 homozygotes having a 14-fold increase in their lifetime risk of developing LOAD compared with APOE-e2 and e3 carriers 24,25 . APOE is the main cholesterol transporter in the brain 16 and the APOE-e4 isoform is thought to have fewer molecules to deliver cholesterol required for myelin and synaptic repair 16,26 .…”
A family history (FH) of dementia, APOE-e4 genotype, and obesity are major risk factors for developing Alzheimer's disease but their combined effects on the brain and cognition remain elusive. We tested the hypothesis that these risk factors affect apparent white matter (WM) myelin and cognition including spatial navigation and processing speed in 166 asymptomatic individuals (38-71 years). Microstructure in temporal [fornix, parahippocampal cingulum, uncinate fasciculus], motor and whole-brain WM was assessed with myelin-sensitive indices from quantitative magnetization transfer [macromolecular proton fraction (MPF)] and axon density from diffusion imaging. Individuals with the highest genetic risk compared to those with FH+ alone showed obesity-related reductions in MPF and axon density in the right parahippocampal cingulum. No effects were present for those without FH.Furthermore, FH modulated obesity-related effects on spatial navigation behaviour. In summary, an individual's genetic dementia risk influenced the impact of obesity on WM myelin and cognition. quantitative magnetization transfer, NODDI, white matter, myelin, parahippocampal cingulum 7
ResultsInsert Table 2 and Figures 2 and 3 here 2.1 Multivariate covariance analysis (MANCOVA) of white matter microstructural indices MANCOVA tested for the effects of APOE genotype (e4+, e4-), family history (FH+, FH-) and central obesity (WHR+, WHR-) on all microstructural indices (MPF, kf, R1, ISOSF, ICSF, ODI) in all white matter pathways (left PHC, right PHC, left UF, right UF, left CST, right CST and fornix) and WBWM regions whilst controlling for age, sex, and years of education. Omnibus effects: Main effects were observed for age [F(48,60) = 2.64, p < 0.001, hp 2 = 0.68] and sex [F(48,60) = 2.61, p < 0.001, hp 2 = 0.67]. Interaction effects were present between APOE and WHR [F(48,60) = 1.6, p = 0.04, hp 2 = 0.56] and between APOE, FH and WHR [F(48,60) = 1.7, p = 0.02, hp 2 = 0.58].Post-hoc effects: Ageing was associated with reductions in MPF, kf, and R1 in WBWM, fornix and right UF (Table 2). MPF and kf reductions were also present in the left UF and bilateral CST respectively. In addition, age-related increases in ISOSF were observed in WBWM and fornix and increases in ODI in the fornix (Table 2, Figure 2A).Women relative to men showed lower kf, ISOSF and ODI in WBWM and the fornix and larger fornix MPF (Table 2, Figure 2B). Two-way interaction effects between APOE and WHR were present for right PHC ( Figure 3A) and bilateral CST but additional post-hoc group comparisons to assess the directions of these effects were non-significant. Three-way interaction effects between FH, APOE and WHR were observed for MPF in WBWM, bilateral CST, bilateral UF and right PHC ( Figure 3B). For right PHC there was also an effect on ICSF. These three-way interaction effects were followed up by testing for APOE and WHR interactions in FH+ and FH-individuals separately ( Figure 3C). FH-individuals did not show any interaction effects B from the Alzheimer's Society and the BR...
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