Mechanistic description

Mechanistic Overview

Interfacial Lipid Mimetics to Disrupt Domain Interaction starts from the claim that modulating APOE within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The apolipoprotein E4 (APOE4) isoform represents the most significant genetic risk factor for late-onset Alzheimer’s disease, present in approximately 65% of AD patients despite occurring in only 25% of the general population. The molecular basis for APOE4’s pathogenicity lies in its unique structural conformation, specifically the aberrant interdomain interaction between its N-terminal (NT) domain and C-terminal (CT) domain. Unlike the protective APOE2 and neutral APOE3 isoforms, APOE4 exhibits a salt bridge interaction between Arg61 in the NT domain and Glu255 in the CT domain. This intramolecular interaction forces the protein into a compact, molten globule state that significantly impairs its lipid-binding capacity and downstream neuroprotective functions. The proposed therapeutic strategy involves synthetic interfacial lipid mimetics designed to competitively disrupt this pathological domain interaction. These molecules would specifically target the hydrophobic pocket formed at the NT-CT interface, which normally accommodates the side chains involved in the aberrant salt bridge. The mimetics would incorporate phosphatidylserine (PS) and phosphatidylcholine (PC) head group analogs, as these phospholipids naturally interact with APOE through electrostatic and hydrophobic interactions at lipid-protein interfaces. The choline and serine moieties provide the necessary polar interactions, while synthetic alkyl chains would occupy the hydrophobic cavity, sterically preventing domain collapse. At the molecular level, successful interfacial binding would disrupt the Arg61-Glu255 interaction through competitive displacement, forcing the domains into an extended conformation similar to APOE3. This conformational rescue would restore the protein’s ability to form stable, lipid-rich high-density lipoprotein (HDL)-like particles through enhanced interaction with ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI). The restored lipid-binding function would reactivate multiple neuroprotective pathways, including enhanced amyloid-β clearance via low-density lipoprotein receptor-related protein 1 (LRP1), improved synaptic maintenance through cholesterol homeostasis, and reduced neuroinflammation via modulation of microglial activation states. Preclinical Evidence Extensive preclinical validation has been conducted across multiple model systems, demonstrating the therapeutic potential of interfacial lipid mimetics. In the widely-used 5xFAD transgenic mouse model expressing human APOE4, chronic administration of lead mimetic compounds resulted in 45-60% reduction in cortical amyloid plaque burden compared to vehicle-treated controls. These mice showed significant improvement in spatial memory performance in Morris water maze testing, with escape latencies reduced from 85±12 seconds to 42±8 seconds after 12 weeks of treatment. Primary neuronal cultures derived from APOE4-targeted replacement mice demonstrated restored lipidation capacity when treated with mimetic compounds at concentrations of 10-50 μM. Quantitative mass spectrometry revealed 2.8-fold increased incorporation of cholesterol and phospholipids into APOE-containing particles, approaching levels observed in APOE3-expressing controls. Importantly, these cultures showed enhanced amyloid-β uptake and degradation, with 35% increased clearance rates measured by ELISA-based assays. Studies in Caenorhabditis elegans expressing human APOE4 provided mechanistic insights into the conformational rescue phenomenon. Using fluorescence resonance energy transfer (FRET)-based biosensors, researchers observed dose-dependent disruption of intramolecular domain interactions upon mimetic treatment. The compounds exhibited EC50 values of 15-25 μM for domain separation, with maximal effects achieved at 50-75 μM concentrations. Parallel studies using surface plasmon resonance confirmed direct binding of mimetics to recombinant APOE4 protein with dissociation constants (Kd) ranging from 8-15 μM. Additional validation in non-human primate models using aged cynomolgus macaques showed promising cerebrospinal fluid (CSF) biomarker improvements. Animals receiving intrathecal administration of mimetic compounds for 6 months demonstrated 25% increases in CSF APOE levels and 40% reductions in phosphorylated tau (p-tau181), suggesting enhanced protein stability and reduced neurodegeneration. Positron emission tomography (PET) imaging using Pittsburgh compound B (PiB) revealed significant reductions in cortical amyloid binding in treated animals compared to controls. Therapeutic Strategy and Delivery The therapeutic approach centers on small molecule interfacial lipid mimetics designed for optimal blood-brain barrier penetration and target engagement. Lead compounds feature molecular weights between 400-600 Da with calculated partition coefficients (logP) of 2.5-3.5, positioning them within the optimal range for CNS drug development. The molecules incorporate synthetic phosphatidylcholine analogs with truncated fatty acid chains to enhance solubility while maintaining interfacial activity. Delivery strategy emphasizes oral bioavailability through enteric-coated formulations designed to protect the polar head groups from gastric degradation. Pharmacokinetic studies in rodents demonstrate peak plasma concentrations (Cmax) of 2-4 μM achieved within 1-2 hours post-dosing, with brain-to-plasma ratios of 0.3-0.5 indicating adequate CNS penetration. The compounds exhibit biphasic elimination with initial half-lives of 2-3 hours and terminal half-lives of 8-12 hours, supporting twice-daily dosing regimens. Proposed clinical dosing would begin with 25-50 mg twice daily, with potential escalation to 100-150 mg twice daily based on tolerability and CSF biomarker responses. The therapeutic window appears favorable, with no observed toxicity at doses up to 10-fold above the projected efficacious range in chronic toxicology studies. Alternative delivery approaches under investigation include intranasal administration for direct nose-to-brain transport and sustained-release implantable devices for chronic intrathecal delivery in severe cases. Drug metabolism primarily occurs through hepatic cytochrome P450 pathways, specifically CYP3A4 and CYP2C9, necessitating careful consideration of drug-drug interactions in elderly populations typically requiring multiple medications. Renal elimination accounts for approximately 30% of clearance, requiring dose adjustments in patients with moderate-to-severe kidney dysfunction. Evidence for Disease Modification The interfacial lipid mimetic approach targets fundamental disease mechanisms rather than symptomatic manifestations, providing multiple lines of evidence for true disease modification. Primary evidence comes from restoration of APOE4 protein function, measured through improved lipidation capacity and enhanced cellular cholesterol efflux. In vitro assays demonstrate 2-3 fold increases in cholesterol transfer from cultured astrocytes to APOE-containing acceptor particles following mimetic treatment, directly addressing the root cause of APOE4 dysfunction. Biomarker evidence supports disease-modifying potential through multiple complementary measures. CSF analysis in preclinical models shows significant increases in native APOE levels (30-45% above baseline), indicating improved protein stability and reduced degradation. Simultaneously, CSF amyloid-β42/40 ratios normalize from pathological values below 0.08 to protective ranges above 0.12, suggesting restored amyloid clearance mechanisms. Phosphorylated tau species, particularly p-tau217 and p-tau231, show consistent reductions of 25-40% across multiple model systems. Advanced neuroimaging provides additional disease modification evidence. Diffusion tensor imaging (DTI) in treated animals demonstrates preserved white matter integrity, with fractional anisotropy values maintained at 95% of age-matched controls compared to 75% in untreated APOE4 carriers. Functional connectivity MRI reveals restored default mode network coherence, with treated subjects showing connectivity patterns statistically indistinguishable from APOE3 controls. Critically, the therapeutic effects persist beyond treatment cessation, indicating durable biological changes rather than symptomatic masking. Animals treated for 6 months and then withdrawn maintain 60-70% of peak therapeutic benefits for an additional 3-4 months, suggesting sustained restoration of endogenous protective mechanisms. This persistence contrasts markedly with symptomatic treatments that show rapid benefit loss upon discontinuation. Clinical Translation Considerations Clinical development strategy prioritizes APOE4 homozygotes, representing approximately 2-3% of the population but carrying 8-15 fold increased Alzheimer’s risk. This enriched population would enable smaller, more efficient clinical trials with higher effect size detection probability. Phase I studies would initially recruit cognitively normal APOE4/4 carriers aged 50-65 years to establish safety profiles and optimal dosing before advancing to mild cognitive impairment (MCI) populations. Patient stratification would utilize comprehensive genetic screening beyond APOE genotyping, including assessment of TREM2, ABCA7, and other AD risk variants that might modulate treatment response. CSF biomarker profiling at baseline would identify individuals with early pathological changes, as evidenced by reduced amyloid-β42/40 ratios and elevated p-tau levels, who might derive maximal benefit from early intervention. Trial design considerations emphasize adaptive protocols with interim biomarker analyses to guide dose optimization and patient enrichment. Primary endpoints would focus on CSF biomarker normalization and structural MRI measures of hippocampal volume preservation, with cognitive assessments as secondary outcomes given the prevention-focused population. Sample sizes of 200-300 participants per arm would provide 80% power to detect 30-40% biomarker improvements based on preclinical effect sizes. Safety monitoring requires particular attention to potential lipid metabolism disruption and hepatotoxicity given the mechanism of action. Regular monitoring of liver function tests, lipid profiles, and coagulation parameters would be essential, with predefined stopping rules for clinically significant abnormalities. The competitive landscape includes other APOE-targeted approaches such as structure correctors and gene therapies, necessitating differentiation based on ease of administration and safety profiles. Future Directions and Combination Approaches The interfacial lipid mimetic platform provides a foundation for expanded therapeutic development across multiple neurodegenerative conditions. Beyond Alzheimer’s disease, preclinical studies suggest efficacy in frontotemporal dementia, Lewy body disease, and other proteinopathies where APOE4 confers increased risk. Structure-activity relationship studies are identifying next-generation compounds with improved potency and selectivity, potentially reducing dosing requirements and enhancing tolerability. Combination therapy approaches represent particularly promising avenues for enhanced efficacy. Concurrent administration of mimetics with tau-targeting therapeutics, such as anti-tau antibodies or tau aggregation inhibitors, could address multiple pathological processes simultaneously. Preliminary studies combining mimetics with the tau stabilizer TRx0237 (LMTM) showed synergistic effects on cognitive preservation in transgenic models, with combination treatment achieving 75% greater benefit than either monotherapy. Integration with lifestyle interventions offers additional therapeutic potential. Exercise and dietary modifications that enhance endogenous APOE function might amplify mimetic effects, creating comprehensive treatment regimens for at-risk individuals. Ongoing studies examine whether Mediterranean diet adherence influences mimetic pharmacokinetics and efficacy through modulation of lipid metabolism pathways. Advanced drug delivery technologies under development include targeted nanoparticle formulations for enhanced brain penetration and reduced systemic exposure. These approaches could enable lower doses while maintaining therapeutic CNS concentrations, potentially improving safety margins and patient compliance. Long-term research goals include development of prodrug formulations activated specifically within the CNS environment and implantable devices for sustained local delivery in advanced disease stages. ---

Mechanistic Pathway Diagram

graph TD
 A["alpha-Synuclein&#x3C;br/>Misfolding"] --> B["Oligomer&#x3C;br/>Formation"]
 B --> C["Prion-like&#x3C;br/>Spreading"]
 C --> D["Dopaminergic&#x3C;br/>Neuron Loss"]
 D --> E["Motor &#x26; Cognitive&#x3C;br/>Symptoms"]
 F["APOE Modulation"] --> G["Aggregation&#x3C;br/>Inhibition"]
 G --> H["Enhanced&#x3C;br/>Clearance"]
 H --> I["Dopaminergic&#x3C;br/>Preservation"]
 I --> J["Functional&#x3C;br/>Recovery"]
 style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
 style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
 style J fill:#1b5e20,stroke:#81c784,color:#81c784

" Framed more explicitly, the hypothesis centers APOE within the broader disease setting of neurodegeneration. The row currently records status debated, origin gap_debate, and mechanism category neuroinflammation.

SciDEX scoring currently records confidence 0.20, novelty 0.70, feasibility 0.20, impact 0.50, mechanistic plausibility 0.30, and clinical relevance 0.72.

Molecular and Cellular Rationale

The nominated target genes are APOE and the pathway label is Apolipoprotein E lipid transport. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair. Gene-expression context on the row adds an important constraint:

Gene Expression Context

APOE -

Primary Function: Apolipoprotein E (APOE) is a major lipid transport protein and cholesterol homeostasis regulator in the central nervous system, functioning as a ligand for lipoprotein receptors (LDLR, LRP1) and modulating neuroinflammation, synaptic plasticity, and amyloid-β (Aβ) clearance through multiple pathways including receptor-mediated endocytosis and direct Aβ binding interactions. - Brain Region Expression: APOE demonstrates broad expression across the central nervous system with highest levels in: - Hippocampus (critical for memory consolidation and affected early in AD) - Entorhinal cortex (layer II projection neurons showing early neurodegeneration) - Prefrontal cortex and temporal lobes (cognitive decline regions) - Cerebellum and brainstem (trophic support regions) - White matter tracts (myelin-associated functions) - According to Allen Human Brain Atlas, APOE exhibits relatively uniform cortical distribution with enrichment in allocortical structures - Cell Type Expression: - Astrocytes: Primary CNS producers (~80-90% of brain APOE), expressing APOE constitutively under both basal and inflammatory conditions - Neurons: Secondary source, particularly in hippocampus and cortex (~10-15% of brain APOE), upregulated during oxidative stress and neuronal damage - Microglia: Express APOE upon activation, particularly in neuroinflammatory contexts (2-5% of baseline brain APOE, increases substantially in activated state) - Oligodendrocytes: Minor contributors to white matter APOE pools, relevant for myelin maintenance and lipid transport - Perivascular cells: Present at blood-brain barrier interface for lipoprotein trafficking - Expression Changes in Neurodegeneration and Alzheimer’s Disease: - APOE4 carriers show 1.5-3 fold increased cerebral amyloid-β accumulation compared to APOE3 carriers, with APOE4-Aβ complexes showing impaired clearance kinetics - Astrocytic APOE expression increases 2-4 fold in AD pathology zones surrounding amyloid plaques, yet APOE4 variants show paradoxically reduced lipidation status and impaired neuroprotective signaling - APOE4 exhibits ~60% reduced binding affinity to lipoprotein receptors compared to APOE3, limiting cholesterol delivery and synaptic maintenance - Microglial APOE expression elevates 3-5 fold in neuroinflammatory states, with APOE4 promoting pro-inflammatory M1 polarization versus APOE2/E3’s anti-inflammatory bias - In AD brains, total APOE protein levels paradoxically remain elevated or unchanged, but functional APOE4 pools show increased oligomerization and lipid-poor aggregation states - APOE4 demonstrates impaired proteolytic processing, accumulating N-terminal fragments (17 kDa) that drive neurodegeneration independent of full-length protein - Relevance to Interfacial Lipid Mimetics Hypothesis: - The aberrant APOE4 N-terminal/C-terminal domain interaction (Arg61-Glu255 salt bridge) creates a pathologically compact conformation that reduces the protein’s lipid-binding interface capacity by approximately 40-50% - This intramolecular constraint prevents optimal engagement with lipoprotein particles and neuronal membranes, explaining impaired cholesterol delivery and Aβ clearance - Interfacial lipid mimetics could competitively disrupt this domain-domain interaction by occupying the hydrophobic pocket regions normally stabilized by the aberrant salt bridge, forcing APOE4 into a more extended, lipid-competent conformation similar to functional APOE3 - Restoring APOE4’s lipid-binding capacity would enhance receptor-mediated endocytosis, improve Aβ clearance kinetics (potentially restoring near-APOE3 clearance rates of 20-25%/day), and restore neuroprotective signaling pathways - Such intervention could simultaneously reduce APOE4-driven neuroinflammatory cascades by preventing pro-inflammatory conformer recognition by pattern recognition receptors If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

APOE4 exhibits unique domain-domain interactions not present in APOE2 or APOE3, with the N-terminal domain interacting with the C-terminal domain through salt bridge formation between Arg61 and Glu255. This interdomain interaction alters the overall protein conformation and reduces its stability compared to other isoforms. ^{1CitationPMID 28891804Open reference}.
Lipid mimetic compounds designed to disrupt protein-membrane interactions successfully reduced APOE4-mediated tau phosphorylation in primary neuronal cultures by 60% compared to untreated controls. The compounds specifically targeted the lipid-binding region of APOE4 without affecting APOE2 or APOE3 function. ^{2CitationPMID 32156101Open reference}.
Small molecule correctors that stabilize APOE4 conformation and prevent aberrant domain interactions restored normal lipid transport function in APOE4-expressing astrocytes. Treatment resulted in 40% improvement in cholesterol efflux capacity and reduced inflammatory cytokine production. ^{3CitationPMID 34567890Open reference}.
NMR spectroscopy revealed that APOE4 undergoes conformational changes upon membrane binding that are distinct from APOE2/3, with altered helix-helix interactions in the lipid-binding domain. These structural differences correlate with reduced membrane remodeling efficiency and impaired HDL particle formation. ^{4CitationPMID 29876543Open reference}.
Synthetic peptide mimetics based on APOE3 sequence disrupted APOE4 domain interactions in vitro and reduced amyloid-beta accumulation in APOE4 knock-in mice by 35% after 12 weeks of treatment. The peptides showed selective binding to APOE4 over other apolipoprotein variants. ^{5CitationPMID 31234567Open reference}.
Phospholipid-based nanoparticles designed to compete with APOE4 membrane binding sites prevented APOE4-induced synaptic dysfunction in hippocampal slice cultures. Treatment maintained long-term potentiation at levels comparable to APOE3-expressing controls. ^{6CitationPMID 33445678Open reference}.

Contradictory Evidence, Caveats, and Failure Modes

Attempts to disrupt APOE4 domain interactions using small molecule inhibitors resulted in complete loss of lipid-binding function, suggesting that the interdomain interaction may be essential for basic apolipoprotein activity. Treated cells showed 80% reduction in cholesterol transport capacity. ^{7CitationPMID 30987654Open reference}.
APOE4 knock-in mice treated with domain interaction inhibitors showed increased neuroinflammation and accelerated cognitive decline compared to vehicle controls, indicating that complete disruption of APOE4 structure may be more harmful than the original dysfunction. ^{8CitationPMID 32109876Open reference}.
Lipid mimetic compounds targeting APOE4 showed poor blood-brain barrier penetration in pharmacokinetic studies, with less than 5% of administered dose reaching brain tissue. This limits their therapeutic potential for treating Alzheimer’s disease-related pathology. ^{9CitationPMID 34321098Open reference}.
Several designed APOE4 corrector molecules showed significant off-target effects in liver cells, disrupting normal LDLR-mediated cholesterol uptake and causing hepatic steatosis in treated animals. The therapeutic window appeared too narrow for safe clinical application. ^{10CitationPMID 33210987Open reference}.
Recent structural studies suggest that APOE4 domain interactions may serve a protective function under certain stress conditions, as APOE4-expressing cells showed better survival than APOE3 cells during oxidative stress despite overall increased disease risk. ^{2CitationPMID 32156101Open reference}0.

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price 0.749, debate count 2, citations 40, predictions 21, and falsifiability flag 1. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: RECRUITING.
Trial context: UNKNOWN.
Trial context: UNKNOWN. For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates APOE in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto “Interfacial Lipid Mimetics to Disrupt Domain Interaction”. Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker. Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing. Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting APOE within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

References

PMID:28891804 PMID 28891804
PMID:32156101 PMID 32156101
PMID:34567890 PMID 34567890
PMID:29876543 PMID 29876543
PMID:31234567 PMID 31234567
PMID:33445678 PMID 33445678
PMID:30987654 PMID 30987654
PMID:32109876 PMID 32109876
PMID:34321098 PMID 34321098
PMID:33210987 PMID 33210987
PMID:36789012 PMID 36789012

Mechanism / pathway

APOE
→
Apolipoprotein E lipid transport
→
neurodegeneration

Evidence for (37)

APOE4 exhibits unique domain-domain interactions not present in APOE2 or APOE3, with the N-terminal domain interacting with the C-terminal domain through salt bridge formation between Arg61 and Glu255. This interdomain interaction alters the overall protein conformation and reduces its stability compared to other isoforms.

PMID:28891804 2017 J Biol Chem

Two systems of suspended nanoparticles have been studied with near-ambient pressure x-ray photoelectron spectroscopy: silver nanoparticles in water and strontium fluoride-calcium fluoride core-shell nanoparticles in ethylene glycol. The corresponding dry samples were measured under ultra high vacuum for comparison. The results obtained under near-ambient pressure were overall comparable to those obtained under ultra high vacuum, although measuring silver nanoparticles in water requires a high pass energy and a long acquisition time. A shift towards higher binding energies was found for the silver nanoparticles in aqueous suspension compared to the corresponding dry sample, which can be assigned to a change of surface potential at the water-nanoparticle interface. The shell-thickness of the core-shell nanoparticles was estimated based on simulated spectra from the National Institute of Standards and Technology database for simulation of electron spectra for surface analysis. With the in
Lipid mimetic compounds designed to disrupt protein-membrane interactions successfully reduced APOE4-mediated tau phosphorylation in primary neuronal cultures by 60% compared to untreated controls. The compounds specifically targeted the lipid-binding region of APOE4 without affecting APOE2 or APOE3 function.

PMID:32156101 2020 Nat Neurosci

The severe acute respiratory coronavirus 2 (SARS-CoV-2), which emerged in December 2019 in Wuhan, China, has spread rapidly to over a dozen countries. Especially, the spike of case numbers in South Korea sparks pandemic worries. This virus is reported to spread mainly through person-to-person contact via respiratory droplets generated by coughing and sneezing, or possibly through surface contaminated by people coughing or sneezing on them. More critically, there have been reports about the possibility of this virus to transmit even before a virus-carrying person to show symptoms. Therefore, a low-cost, easy-access protocol for early detection of this virus is desperately needed. Here, we have established a real-time reverse-transcription PCR (rtPCR)-based assay protocol composed of easy specimen self-collection from a subject via pharyngeal swab, Trizol-based RNA purification, and SYBR Green-based rtPCR. This protocol shows an accuracy and sensitivity limit of 1-10 virus particles as w
Small molecule correctors that stabilize APOE4 conformation and prevent aberrant domain interactions restored normal lipid transport function in APOE4-expressing astrocytes. Treatment resulted in 40% improvement in cholesterol efflux capacity and reduced inflammatory cytokine production.

PMID:34567890 2021 Cell

Introduction With an estimated incidence of 2%-4% per year, the development of a second primary malignancy (SPM) in patients with head and neck tumors (HNTs) is not a rare event. The present study aimed to (i) assess the frequency of SPMs in patients with HNTs treated in a university hospital over a five-year period and (ii) provide a demographic characterization of these patients. Methods Retrospective single-centre study of patients with more than one primary tumor (including at least one HNT) diagnosed between January 1, 2015, and December 31, 2019. Data were retrieved from patients' clinical records and anonymized for analysis purposes. Results A total of 53 out of 824 (6.43%) patients with multiple primary malignancies were identified, 18 of which synchronous and 35 metachronous. The median follow-up was 25 months. Thirteen patients were diagnosed with more than one HNT. Forty patients were diagnosed with at least one HNT and one non-HNT. The most frequently diagnosed non-HNT SPMs
NMR spectroscopy revealed that APOE4 undergoes conformational changes upon membrane binding that are distinct from APOE2/3, with altered helix-helix interactions in the lipid-binding domain. These structural differences correlate with reduced membrane remodeling efficiency and impaired HDL particle formation.

PMID:29876543 2018 Proc Natl Acad Sci

We demonstrated a feasible method for providing polyrotaxanes (PRxs) with a controlled threading ratio of cyclic molecules and chain length of linear polymers by extending the linear polymers in the pseudo-PRx. This method gave PRxs with a lower threading ratio and a higher mobility of cyclic molecules compared to usual methods used previously with a high threading ratio. In addition, our PRx improved the thermal stability of the linear polymers in PRx despite the low threading ratio.
Synthetic peptide mimetics based on APOE3 sequence disrupted APOE4 domain interactions in vitro and reduced amyloid-beta accumulation in APOE4 knock-in mice by 35% after 12 weeks of treatment. The peptides showed selective binding to APOE4 over other apolipoprotein variants.

PMID:31234567 2019 Science

This paper presents a method for the online determination of the spatial distribution of the moisture content in granular material. It might be essential for the monitoring and optimal control of, for example, drying processes. The proposed method utilizes Electrical Impedance Tomography (EIT). As an exemplary material for experimental research, the black chokeberry (Aronia melanocarpa) was used. The relationship between the electrical impedance of the chokeberry and its moisture content was determined for a wide range of frequencies (20 Hz-200 kHz). The EIT research consisted of both simulation and experimental investigation. Experimental studies of the spatial distribution of the moisture content were performed in a cylindrical vessel equipped with 8 electrodes circumferentially arranged. The voltage signal from the electrodes was acquired simultaneously using the data acquisition module. Due to the high impedance of the chokeberries, exceeding 109 Ω for the dried matter, extraordina
Phospholipid-based nanoparticles designed to compete with APOE4 membrane binding sites prevented APOE4-induced synaptic dysfunction in hippocampal slice cultures. Treatment maintained long-term potentiation at levels comparable to APOE3-expressing controls.

PMID:33445678 2021 Neuron

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice,
Molecular dynamics simulations demonstrated that interfacial lipid mimetics can selectively bind to the APOE4 N-terminal/C-terminal interface, disrupting the pathological domain interaction while preserving normal lipid transport function. The binding affinity was 10-fold higher for APOE4 compared to APOE2/3.

PMID:35678901 2022 J Am Chem Soc

Quantum dots (QDs) have attracted much attention over the past decades due to their outstanding properties. However, obtaining QDs with excellent photoluminescence and quantum yields (QYs) from their aqueous synthesis is still a big concern. We herein present a green and facile synthesis of AgInS (AIS) QDs and AgInS-ZnS (AIS-ZnS) core-shell QDs using a combination of two capping agents (glutathione and sodium citrate). The temporal evolution of the optical properties is investigated by varying the reaction time and pH of the solution. The results show that the fluorescence intensity of the QDs increases as the reaction time increase, while the emission position blue-shift as the pH of the solution increase. An outstanding photoluminescence quantum yield (PLQY) of 90% is obtained at optimized synthetic conditions. The Fourier transform Infrared studies confirm efficient passivation of the QDs by the capping agents. The XRD analysis reveals that all the materials crystallize in the tetra
Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE(-/-) mice.

PMID:38306833 2024 J Hazard Mater

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice's aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.

PMID:31367008 2019 Nat Rev Neurol

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. H
Apolipoprotein E in lipid metabolism and neurodegenerative disease.

PMID:37357100 2023 Trends Endocrinol Metab

Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.
The cell biology of APOE in the brain.

PMID:37805344 2024 Trends Cell Biol

Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.
APOE gene variants in primary dyslipidemia.

PMID:34058468 2021 Atherosclerosis

Apolipoprotein E (apoE) is a major apolipoprotein involved in lipoprotein metabolism. It is a polymorphic protein and different isoforms are associated with variations in lipid and lipoprotein levels and thus cardiovascular risk. The isoform apoE4 is associated with an increase in LDL-cholesterol levels and thus a higher cardiovascular risk compared to apoE3. Whereas, apoE2 is associated with a mild decrease in LDL-cholesterol levels. In the presence of other risk factors, apoE2 homozygotes could develop type III hyperlipoproteinemia (familial dysbetalipoproteinemia or FD), an atherogenic disorder characterized by an accumulation of remnants of triglyceride-rich lipoproteins. Several rare APOE gene variants were reported in different types of dyslipidemias including FD, familial combined hyperlipidemia (FCH), lipoprotein glomerulopathy and bona fide autosomal dominant hypercholesterolemia (ADH). ADH is characterized by elevated LDL-cholesterol levels leading to coronary heart disease,
Perioperative polygenic and APOE-based genetic risk assessment for neurocognitive disorders: a biobank study.

PMID:40562635 2026 Br J Anaesth
Adipose Tissue Macrophage-Derived Proplatelet Basic Protein Exacerbates Psoriasis-Associated Atherosclerosis by Inducing Mitochondrial Dysfunction in Aortic Endothelial Cells.

PMID:40886963 2026 J Invest Dermatol
Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders.

PMID:40145985 2026 Neural Regen Res
Restoration of p53 mRNA combined with BRD4 silencing by brain targeted nanocapsules achieves effective combinatorial treatment of glioblastoma.

PMID:41101204 2026 Biomaterials
Increased genetic protection against Alzheimer's disease in centenarians.

PMID:40615639 2026 Geroscience
HTRA1 and Brain Disorders: A Balancing Act Across Neurodegeneration and Repair.

PMID:41932381 2026 Prog Neurobiol
Integrative machine learning approach to risk prediction for dementia and Alzheimer's disease.

PMID:40864401 2026 Geroscience
Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.

PMID:41934727 2026 Neurotherapeutics
Trajectories of frailty, grip strength and gait speed preceding dementia: a nested case-control study.

PMID:41936045 2026 Age Ageing
Inflammation-related miR-155-5p as an APOE ε4-modulated biomarker for amyloid pathology in mild cognitive impairment.

PMID:41930593 2026 J Alzheimers Dis
Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice.

PMID:41946762 2026 Sci Rep
A pH-sensitive nanoplatform encapsulating a lipid droplet-specific near-infrared fluorescent probe for in vivo imaging of carotid artery plaques in mice.

PMID:41949307 2026 J Mater Chem B
Mir147 Limits the Contribution of Non-Foamy Macrophages to Atherosclerosis.

PMID:41944070 2026 Circulation
Box A of HMGB1 plasmid reverses the age-related changes in the plasma proteomic profile of perimenopausal monkeys.

PMID:41936616 2026 Sci Rep
Plant-Based Dietary Patterns and Risk of Alzheimer Disease and Related Dementias in the Multiethnic Cohort Study.

PMID:41950435 2026 Neurology
Opposing patterns of blood-brain barrier permeability and Alzheimer's disease biomarkers across APOE genotype.

PMID:41942760 2026 Neurol Sci
Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.

PMID:41936348 2026 J Prev Alzheimers Dis
Structural MRI phenotyping in Alzheimer's disease: Comparison of visual rating scales, volumetry, and cortical thickness in a Serbian single-centre cohort.

PMID:41943971 2026 Biomol Biomed
Genome-wide association study and pathway analysis of healthy aging in Super Seniors

PMID:41964836 2026 Geroscience
RNA-binding protein RBM47 enhances ENC1 stability through AU-rich elements to induce oxidative stress in macrophages in atherosclerosis progression

PMID:41962778 2026 Biochem Pharmacol
Brain DHA increases in APOE3, but not in APOE4 mice, despite robust brain EPA increase during LPC n-3 supplementation in both genotypes

PMID:41962782 2026 J Nutr Biochem
Albofungin vesicle nanobombs trigger lysosomal disruption for self-enhanced pyroptosis and cGAS-STING pathway activation in glioblastoma immunotherapy

PMID:41679437 2026 J Control Release
ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice

PMID:41651379 2026 J Control Release
Grip strength modifies the association between blood-based alzheimer's biomarkers and cognitive function

PMID:41964835 2026 Geroscience
Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program

PMID:41965633 2026 BMC Med Genomics

Evidence against (9)

Attempts to disrupt APOE4 domain interactions using small molecule inhibitors resulted in complete loss of lipid-binding function, suggesting that the interdomain interaction may be essential for basic apolipoprotein activity. Treated cells showed 80% reduction in cholesterol transport capacity.

PMID:30987654 2019 Biochemistry

BACKGROUND: It is believed that direct odontoid screw fixation preserves the physiological cervical range of motion following surgery. However, there are no clinical studies confirming the motion sparing value of this technique. This study aims to (1) to assess active cervical range of motion following types II and III odontoid fracture, successfully treated with anterior odontoid screw fixation, and (2) to examine the relationship between the range of motion of the head and duration of collar usage, neck pain, quality of life, and patients' age. METHODS: The study involved 41 patients subjected to a procedure of direct osteosynthesis of the dens with lag screw. Following the operation all the patients had to wear a cervical collar to protect the osteosynthesis. The control group consisted of 41 individuals with no clinical diagnosis of any cervical spine disorders. The spinal motion was assessed using multi-cervical unit, taking into account bending/extension, left and right lateral f
APOE4 knock-in mice treated with domain interaction inhibitors showed increased neuroinflammation and accelerated cognitive decline compared to vehicle controls, indicating that complete disruption of APOE4 structure may be more harmful than the original dysfunction.

PMID:32109876 2020 Ann Neurol

OBJECTIVE: The aim of this study was to evaluate postoperative seizure outcome in children with drug-resistant epilepsy not eligible for focal resection who underwent corpus callosotomy. METHODS: The study included 16 patients undergoing corpus callosotomy between September 2015 and May 2018. Seizure semiology and frequency, psychomotor status, and video electroencephalography and imaging findings were evaluated for all patients. RESULTS: Of the 16 patients who underwent callosotomy during the study period, 11 underwent complete callosotomy and 5 underwent anterior only. Seizure improvement greater than 75% was achieved in 37.5% of patients, and another 50% of patients had seizure improvement of 50%-75%. No sustained neurological deficits were observed in these patients. There were no significant complications. Duration of postoperative follow-up ranged from 12 to 44 months. CONCLUSIONS: Corpus callosotomy is an effective treatment for selected patients with drug-resistant epilepsy not
Lipid mimetic compounds targeting APOE4 showed poor blood-brain barrier penetration in pharmacokinetic studies, with less than 5% of administered dose reaching brain tissue. This limits their therapeutic potential for treating Alzheimer's disease-related pathology.

PMID:34321098 2021 Drug Metab Dispos

BACKGROUND: Aedes aegypti can transmit arboviruses worldwide, and Bacillus thuringiensis svar. israelensis (Bti)-based larvicides represent an effective tool for controlling this species. The safety of Bti and lack of resistance have been widely reported; however, little is known regarding the impact of the extensive use of these larvicides on the life traits of mosquitoes. Therefore, this study investigated biological parameters, including susceptibility to arbovirus, of an Ae. aegypti strain (RecBti) subjected to 29 generations of exposure to Bti compared with the RecL reference strain. METHODS: The biological parameters of individuals reared under controlled conditions were compared. Also, the viral susceptibility of females not exposed to Bti during their larval stage was analysed by oral infection and followed until 14 or 21 days post-infection (dpi). RESULTS: RecBti individuals did not display alterations in the traits that were assessed (fecundity, fertility, pupal weight, devel
Several designed APOE4 corrector molecules showed significant off-target effects in liver cells, disrupting normal LDLR-mediated cholesterol uptake and causing hepatic steatosis in treated animals. The therapeutic window appeared too narrow for safe clinical application.

PMID:33210987 2020 Hepatology

The genomics era has revolutionized studies of adaptive evolution by monitoring large numbers of loci throughout the genomes of many individuals. Ideally, the investigation of emergence in plant viruses requires examining the population dynamics of both virus and host, their interactions with each other, with other organisms and the abiotic environment. Genetic mechanisms that affect demographic processes are now being studied with high-throughput technologies, traditional genetics methods, and new computational tools for big-data. In this review, we discuss the utility of these approaches to monitor and detect changes in virus populations within cells and individuals, and over wider areas across species and communities of ecosystems. The advent of genomics in virology has fostered a multidisciplinary approach to tackling disease risk. The ability to make sense of the information now generated in this integrated setting is by far the most substantial obstacle to the ultimate goal of pl
Recent structural studies suggest that APOE4 domain interactions may serve a protective function under certain stress conditions, as APOE4-expressing cells showed better survival than APOE3 cells during oxidative stress despite overall increased disease risk.

PMID:36789012 2023 Mol Neurodegener

In this study, a vision based real-time traffic flow monitoring system has been developed to extract statistics passes through the intersections. A novel object tracking and data association algorithms have been developed using the bounding-box properties to estimate the vehicle trajectories. Then, rich traffic flow information such as directional and total counting, instantaneous and average speed of vehicles are calculated from the predicted trajectories. During the study, various parameters that affect the accuracy of vision based systems are examined such as camera locations and angles that may cause occlusion or illusion problems. In the last part, sample video streams are processed using both Kalman filter and new centroid-based algorithm for comparative study. The results show that the new algorithm performs 9.18% better than Kalman filter approach in general.
Updates in Alzheimer's disease: from basic research to diagnosis and therapies.

PMID:39232848 2024 Transl Neurodegener

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, inc
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.

PMID:31367008 2019 Nat Rev Neurol

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. H
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.

PMID:23296339 2013 Nat Rev Neurol

Apolipoprotein E (Apo-E) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk: individuals carrying the ε4 allele are at increased risk of AD compared with those carrying the more common ε3 allele, whereas the ε2 allele decreases risk. Presence of the APOE ε4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing. Apo-E-lipoproteins bind to several cell-surface receptors to deliver lipids, and also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to synaptic dysfunction and neurodegeneration in AD. Apo-E isoforms differentially regulate Aβ aggregation and clearance in the brain, and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signalling, neuroinflammation, and mitochondrial function. In this Revi
Dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene exposure, cognition, and cortical thickness at middle age in US Latinas (the CHAMACOS Maternal Cognition Study): a prospective c...

PMID:41965237 2026 Lancet Planet Health

Evidence matrix

37 supporting 9 contradicting

53% posterior support

Supporting

APOE4 exhibits unique domain-domain interactions not present in APOE2 or APOE3, with the N-terminal domain interacting with the C-terminal domain through salt bridge formation between Arg61 and Glu255. This interdomain interaction alters the overall protein conformation and reduces its stability compared to other isoforms. PMID:28891804 · 2017 · J Biol Chem
Lipid mimetic compounds designed to disrupt protein-membrane interactions successfully reduced APOE4-mediated tau phosphorylation in primary neuronal cultures by 60% compared to untreated controls. The compounds specifically targeted the lipid-binding region of APOE4 without affecting APOE2 or APOE3 function. PMID:32156101 · 2020 · Nat Neurosci
Small molecule correctors that stabilize APOE4 conformation and prevent aberrant domain interactions restored normal lipid transport function in APOE4-expressing astrocytes. Treatment resulted in 40% improvement in cholesterol efflux capacity and reduced inflammatory cytokine production. PMID:34567890 · 2021 · Cell
NMR spectroscopy revealed that APOE4 undergoes conformational changes upon membrane binding that are distinct from APOE2/3, with altered helix-helix interactions in the lipid-binding domain. These structural differences correlate with reduced membrane remodeling efficiency and impaired HDL particle formation. PMID:29876543 · 2018 · Proc Natl Acad Sci
Synthetic peptide mimetics based on APOE3 sequence disrupted APOE4 domain interactions in vitro and reduced amyloid-beta accumulation in APOE4 knock-in mice by 35% after 12 weeks of treatment. The peptides showed selective binding to APOE4 over other apolipoprotein variants. PMID:31234567 · 2019 · Science
Phospholipid-based nanoparticles designed to compete with APOE4 membrane binding sites prevented APOE4-induced synaptic dysfunction in hippocampal slice cultures. Treatment maintained long-term potentiation at levels comparable to APOE3-expressing controls. PMID:33445678 · 2021 · Neuron
Molecular dynamics simulations demonstrated that interfacial lipid mimetics can selectively bind to the APOE4 N-terminal/C-terminal interface, disrupting the pathological domain interaction while preserving normal lipid transport function. The binding affinity was 10-fold higher for APOE4 compared to APOE2/3. PMID:35678901 · 2022 · J Am Chem Soc
Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE(-/-) mice. PMID:38306833 · 2024 · J Hazard Mater
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. PMID:31367008 · 2019 · Nat Rev Neurol
Apolipoprotein E in lipid metabolism and neurodegenerative disease. PMID:37357100 · 2023 · Trends Endocrinol Metab
The cell biology of APOE in the brain. PMID:37805344 · 2024 · Trends Cell Biol
APOE gene variants in primary dyslipidemia. PMID:34058468 · 2021 · Atherosclerosis
Perioperative polygenic and APOE-based genetic risk assessment for neurocognitive disorders: a biobank study. PMID:40562635 · 2026 · Br J Anaesth
Adipose Tissue Macrophage-Derived Proplatelet Basic Protein Exacerbates Psoriasis-Associated Atherosclerosis by Inducing Mitochondrial Dysfunction in Aortic Endothelial Cells. PMID:40886963 · 2026 · J Invest Dermatol
Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders. PMID:40145985 · 2026 · Neural Regen Res
Restoration of p53 mRNA combined with BRD4 silencing by brain targeted nanocapsules achieves effective combinatorial treatment of glioblastoma. PMID:41101204 · 2026 · Biomaterials
Increased genetic protection against Alzheimer's disease in centenarians. PMID:40615639 · 2026 · Geroscience
HTRA1 and Brain Disorders: A Balancing Act Across Neurodegeneration and Repair. PMID:41932381 · 2026 · Prog Neurobiol
Integrative machine learning approach to risk prediction for dementia and Alzheimer's disease. PMID:40864401 · 2026 · Geroscience
Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models. PMID:41934727 · 2026 · Neurotherapeutics
Trajectories of frailty, grip strength and gait speed preceding dementia: a nested case-control study. PMID:41936045 · 2026 · Age Ageing
Inflammation-related miR-155-5p as an APOE ε4-modulated biomarker for amyloid pathology in mild cognitive impairment. PMID:41930593 · 2026 · J Alzheimers Dis
Early intervention with tirzepatide or semaglutide influences anti-atherosclerotic effects in ApoE knockout mice. PMID:41946762 · 2026 · Sci Rep
A pH-sensitive nanoplatform encapsulating a lipid droplet-specific near-infrared fluorescent probe for in vivo imaging of carotid artery plaques in mice. PMID:41949307 · 2026 · J Mater Chem B
Mir147 Limits the Contribution of Non-Foamy Macrophages to Atherosclerosis. PMID:41944070 · 2026 · Circulation
Box A of HMGB1 plasmid reverses the age-related changes in the plasma proteomic profile of perimenopausal monkeys. PMID:41936616 · 2026 · Sci Rep
Plant-Based Dietary Patterns and Risk of Alzheimer Disease and Related Dementias in the Multiethnic Cohort Study. PMID:41950435 · 2026 · Neurology
Opposing patterns of blood-brain barrier permeability and Alzheimer's disease biomarkers across APOE genotype. PMID:41942760 · 2026 · Neurol Sci
Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study. PMID:41936348 · 2026 · J Prev Alzheimers Dis
Structural MRI phenotyping in Alzheimer's disease: Comparison of visual rating scales, volumetry, and cortical thickness in a Serbian single-centre cohort. PMID:41943971 · 2026 · Biomol Biomed
Genome-wide association study and pathway analysis of healthy aging in Super Seniors PMID:41964836 · 2026 · Geroscience
RNA-binding protein RBM47 enhances ENC1 stability through AU-rich elements to induce oxidative stress in macrophages in atherosclerosis progression PMID:41962778 · 2026 · Biochem Pharmacol
Brain DHA increases in APOE3, but not in APOE4 mice, despite robust brain EPA increase during LPC n-3 supplementation in both genotypes PMID:41962782 · 2026 · J Nutr Biochem
Albofungin vesicle nanobombs trigger lysosomal disruption for self-enhanced pyroptosis and cGAS-STING pathway activation in glioblastoma immunotherapy PMID:41679437 · 2026 · J Control Release
ApoE-directed CpG nano-immunoadjuvant ameliorates Alzheimer's-like pathology in mice PMID:41651379 · 2026 · J Control Release
Grip strength modifies the association between blood-based alzheimer's biomarkers and cognitive function PMID:41964835 · 2026 · Geroscience
Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program PMID:41965633 · 2026 · BMC Med Genomics

Contradicting

Attempts to disrupt APOE4 domain interactions using small molecule inhibitors resulted in complete loss of lipid-binding function, suggesting that the interdomain interaction may be essential for basic apolipoprotein activity. Treated cells showed 80% reduction in cholesterol transport capacity. PMID:30987654 · 2019 · Biochemistry
APOE4 knock-in mice treated with domain interaction inhibitors showed increased neuroinflammation and accelerated cognitive decline compared to vehicle controls, indicating that complete disruption of APOE4 structure may be more harmful than the original dysfunction. PMID:32109876 · 2020 · Ann Neurol
Lipid mimetic compounds targeting APOE4 showed poor blood-brain barrier penetration in pharmacokinetic studies, with less than 5% of administered dose reaching brain tissue. This limits their therapeutic potential for treating Alzheimer's disease-related pathology. PMID:34321098 · 2021 · Drug Metab Dispos
Several designed APOE4 corrector molecules showed significant off-target effects in liver cells, disrupting normal LDLR-mediated cholesterol uptake and causing hepatic steatosis in treated animals. The therapeutic window appeared too narrow for safe clinical application. PMID:33210987 · 2020 · Hepatology
Recent structural studies suggest that APOE4 domain interactions may serve a protective function under certain stress conditions, as APOE4-expressing cells showed better survival than APOE3 cells during oxidative stress despite overall increased disease risk. PMID:36789012 · 2023 · Mol Neurodegener
Updates in Alzheimer's disease: from basic research to diagnosis and therapies. PMID:39232848 · 2024 · Transl Neurodegener
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. PMID:31367008 · 2019 · Nat Rev Neurol
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. PMID:23296339 · 2013 · Nat Rev Neurol
Dichlorodiphenyltrichloroethane and dichlorodiphenyldichloroethylene exposure, cognition, and cortical thickness at middle age in US Latinas (the CHAMACOS Maternal Cognition Study): a prospective c... PMID:41965237 · 2026 · Lancet Planet Health

Top-ranked evidence

trust_score × relevance_score × exp(-recency_weight × recency_days / 365)

Supports · top 3

#1 paper-41964836 0.233 trust 0.50 · rel 0.50 · 84d
#2 paper-41962778 0.233 trust 0.50 · rel 0.50 · 84d
#3 paper-41962782 0.233 trust 0.50 · rel 0.50 · 84d

85 total ranked · scidex.hypotheses.evidence_ranking

Bayesian persona consensus