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INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimers disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimers Association convened multidisciplinary researchers at the AAIC Advancements: APOE conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoEs multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimers disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

PURPOSE: To determine whether microstructural retinal changes, tumor features, and apolipoprotein E (APOE) ε4 polymorphism are correlated with clinically detectable treatment-associated cognitive dysfunction (TACD) in patients with lower-grade gliomas. DESIGN: Cohort study. PARTICIPANTS AND CONTROLS: Sixteen patients with lower-grade glioma at a United States academic ophthalmology department between January 2021 and November 2023. Normal controls were recruited from convenient sampling. METHODS: Montreal Cognitive Assessment (MoCA) scores and retinal changes were assessed in 6-month intervals. Apolipoprotein E genotyping was performed, and tumor details were recorded. Partial least-squares discriminant (PLSD) model was established to evaluate the association between TACD with APOE genotype, ophthalmic, and tumor features. MAIN OUTCOME MEASURES: The main outcome measure was cognitive status as measured by the MoCA score and analyzed in relation to ophthalmic measurements, tumor features, and APOE genotype. RESULTS: Median time to first eye examination was 34 months (2-266) from tumor diagnosis and 23 months (0-246) from radiation. Nine patients (56%) had abnormal cognition (MoCA

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

This study assessed whether the effect of vascular risk on cerebral blood flow (CBF) varies by gene dose of apolipoprotein (APOE) ε4 alleles. 144 older adults without dementia from the Alzheimers Disease Neuroimaging Initiative underwent arterial spin labeling and T1-weighted MRI, APOE genotyping, fluorodeoxyglucose positron emission tomography (FDG-PET), lumbar puncture, and blood pressure (BP) assessment. Vascular risk was assessed using pulse pressure (systolic BP - diastolic BP). CBF was examined in six AD-vulnerable regions: entorhinal cortex, hippocampus, inferior temporal cortex, inferior parietal cortex, rostral middle frontal gyrus, and medial orbitofrontal cortex. Linear regressions tested the interaction between APOE ε4 dose and pulse pressure on CBF in each region, adjusting for age, sex, cognitive classification, antihypertensive medication use, FDG-PET, reference CBF region, and AD biomarker positivity. There was a significant interaction between pulse pressure and APOE ɛ4 dose on CBF in the entorhinal cortex, hippocampus, and inferior parietal cortex, such that higher pulse pressure was associated with lower CBF only among ε4 homozygous participants. These findings demonstrate that the association between pulse pressure and regional CBF differs by APOE ε4 dose, suggesting that targeting modifiable vascular risk factors may be particularly important for those genetically at risk for AD.

Background: Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM). Methods: A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history. Results: Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]). Conclusions: Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD. [ABSTRACT FROM AUTHOR]

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = −0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = −0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum. [ABSTRACT FROM AUTHOR]

Background: The causal relationship between familial hypercholesterolemia (FH) and various vitamin deficiencies has not yet been elucidated. Therefore, this study investigated the cause-and-effect relationship between FH and the risk of multiple vitamin deficiencies in humans. Methods: Mendelian randomization (MR) analysis was performed by extracting six datasets for FH, FH with ischemic heart disease (IHD), and vitamin deficiency (vitamin A, thiamine, other B-group vitamins, and vitamin D) from the FinnGen study, covering a total of 329,115; 316,290; 354,932; 354,949; 355,411 and 355,238 individuals, respectively. Results: FH was suggestively associated with higher odds of thiamine deficiency [inverse variance weighted odds ratio (ORIVW) 95% confidence interval (CI): 1.62 (1.03, 2.55), P = 0.036] and vitamin D deficiencies [ORIVW CI: 1.35 (1.04, 1.75), P = 0.024], low-density lipoprotein receptor (LDLR) rs112898275 variant, rs11591147 and rs499883 in proprotein convertase subtilisin/kexin 9 (PCSK9), rs9644862 in cyclin-dependent kinase inhibitor 2 B antisense RNA1 (CDKN2B-AS1), and rs142834163 in dedicator of cytokinesis 6 (DOCK6) and rs115478735 in ABO blood group (ABO) strongly influenced the risk of thiamine deficiency, while the rs7412 variant in apolipoprotein E (APOE) mostly influenced the risk of vitamin D deficiency. FH with IHD was suggestively associated with higher odds of vitamin D deficiency (ORIVW, weighted median [WM][95%CI]: 1.31 [1.05, 1.64]; 1.47 [1.10, 1.97]) (P = 0.018; 0.010) without any single significant SNPs observed. Conclusion: FH was positively associated with increased risks of thiamine and vitamin D deficiencies, revealing a prospective and unfortunate complication of FH. [ABSTRACT FROM AUTHOR]

The composition of the protein corona covering any nanoparticle (NP) when it enters a biological fluid determines the parameters of the NP's interaction with the body. To "control" these parameters, it is important to know the composition of the protein corona, the determination of which is a complex task associated with the two-layer organization of the corona (hard and soft coronas). In a previous publication, we reported obtaining lipid-coated NPs with a full protein corona, isolating them, and proving the presence of the corona on the surface of the NPs. This work reports on the preparation, isolation, and purification of lipid-coated NPs bearing a hard corona. The protein corona composition was determined by using the LC–MS/MS method. Thirty-seven serum proteins were identified with a high degree of reliability. The hard corona contained various apolipoproteins, including apolipoprotein E, which can potentially affect the penetration of NPs into the cell. [ABSTRACT FROM AUTHOR]

The article discusses the initiation of a natural history study of ALS by Target ALS to capture multi-omic, clinical, and demographic datasets linked to longitudinal biofluids. Efforts are made to include historically underrepresented ethnicities and races in the study. The study aims to enroll 800 symptomatic ALS participants and 200 healthy controls from diverse populations worldwide. The study has enrolled 125 participants to date, with 24% of ALS participants known to have genetic mutations. The study also explores the prevalence of ALS in Kazakhstan and the influence of environmental factors on the disease. [Extracted from the article]

Background: Modifiable (physical activity) and non-modifiable (sex and genotype) risk factors interact to affect Alzheimer's disease (AD) risk. Further investigation is necessary to understand if these factors influence brain volume and cognition. Objective: The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. Methods: UK Biobank data from 2006 to 2023 was accessed. Physical activity was measured by accelerometers, and International Physical Activity Questionnaire. Outcomes were AD incidence; brain volume (ventricular cerebrospinal fluid and total brain); and cognition (executive function, memory, visuospatial ability, processing speed, and reaction time). Logistic and linear regression models were conducted. Results: 69,060 participants met inclusion criteria (mean age: 62.28 years, SD: 7.84; 54.64% female). Higher self-reported (OR = 0.63, 95% CI [0.40, 1.00], p = 0.047) and accelerometer-assessed (OR = 0.96 [0.93, 0.98], p = 0.002) physical activity was associated with lower disease incidence. Smaller ventricular cerebrospinal fluid volume (β= – 65.43 [– 109.68, – 17.40], p = 0.007), and larger total brain volume (β= 4398.46 [165.11, 8631.82], p < 0.001) was associated with increased accelerometer-assessed and self-reported physical activity respectively. Both brain volume analyses were moderated by sex. Increased accelerometer-assessed physical activity levels were associated with faster reaction time (β= – 0.43 [– 0.68, – 0.18], p = 0.001); though poorer visuospatial ability (β= – 0.06 [– 0.09, – 0.03], p < 0.001), and executive function (β= 0.49 [0.31, 0.66], p < 0.001; β= 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. Conclusions: Higher levels of physical activity reduce AD risk independently of non-modifiable risk factors. Moderation of sex on brain volume highlighted the importance of incorporating non-modifiable risk factors in analysis. [ABSTRACT FROM AUTHOR]

Background: Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer's disease. Objective: To examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and their ratio (ApoB/ApoA1) are associated with cortical morphology in patients with memory complaints. Methods: Ninety-seven patients underwent neuropsychological testing, measurements of ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer's biomarker, apolipoprotein E (ApoE) genotyping, and 3T structural magnetic resonance imaging (sMRI) scans. Based on sMRI scanning locations, patients were categorized into the University of Electronic Science and Technology (UESTC) and the Fourth People's Hospital of Chengdu (FPHC). The Computational Anatomy Toolbox within Statistical Parametric Mapping was used to calculate each patient's cortical morphology index based on sMRI data. The cortical morphology index and apolipoproteins were also analyzed. Results: Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex among the UESTC, the FPHC, and the total sample groups, and negative correlations were observed between sulcal depth in the lateral occipital cortex and the scores of the Shape Trails Test Part A and B. In the FPHC group, the scores of the Montreal Cognitive Assessment Basic, delayed recall of the Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth. Conclusions: ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints. [ABSTRACT FROM AUTHOR]

Background: Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well-tolerated in cognitively unimpaired (CU) older adults. This study aimed to examine the effect of the disclosure process on decisions about future directives and health behaviors in community-dwelling CU older adults from the Butler Alzheimer's Prevention Registry (BAPR). Methods: CU APOE E4 non-carriers (n = 106) and carriers (n = 80) aged 58-78 completed in-person psychological readiness screening to undergo APOE disclosure. Follow-up assessments were completed online 3 days, 6 weeks, and 6 months post-disclosure. The primary outcomes were future directives, dietary habits, and physical activity scores. Results: Disclosure was associated with decision making on future directives in E4 carriers (t = 3.59, P =.01) at 6 months compared to baseline, but not non-carriers. Family history of memory impairment, SCD endorsement, and education consistently predicted scores on future directives. A significant interaction between E4+ and SCD endorsement on future directive scores was noted (OR = 163.06, 9.5-2,799.8). E4 + carrier status was associated with physical activity (W = 60,148, P =.005) but not dietary habits scores. Conclusions: Our findings indicate that disclosure led to a change in future directives but not protective health behaviors, specifically in E4 carriers. Future work will explore whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk-lowering lifestyle modifications as an intervention approach leads to positive change. [ABSTRACT FROM AUTHOR]

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer's disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0–81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b= − 0.12 , CI= − 0.14 , − 0.10 ) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI= 0.04,0.07 ), demonstrating a significant moderation role of APOE4 (b = − 0.18 , CI= − 0.20 , − 0.15 , P<0.00001). • LDL is negatively associated with white matter integrity in older APOE4 carriers. • This association, although weak, is positive in APOE4 non-carriers. • APOE4 carriers with high LDL show a stronger negative age-cognition correlation. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether individuals with subjective cognitive decline (SCD) have changes in whole-brain network characteristics and intracerebral node characteristics in the structural network, and whether there is a difference between SCD with and without Apolipoprotein E4 (APOEε4). Methods: This cross-sectional study included 36 individuals without SCD without APOEε4 (healthy control, HC group), 21 individuals with SCD with APOEε4 (APOEε4+ group), and 33 individuals with SCD without APOEε4 (APOEε4-group). The white matter structural network was constructed using the fractional anisotropy (FA) based deterministic fiber tracking method. Graph theory was used to analyze the whole-brain network characteristics and intracerebral node characteristics of the three groups. Results: Regarding the whole-brain network characteristics, all three groups exhibited small-worldness in their structural networks. The clustering coefficient (Cp) and local efficiency (Eloc) in the APOEε4+ and APOEε4- groups were significantly lower than in the HC group (p < 0.05), but no significant difference in Cp or Eloc was observed between the APOEε4+ and APOEε4- groups. Regarding intracerebral node characteristics, there were significant differences in some brain regions, mainly the default mode network (DMN), the occipital lobe, the temporal lobe, and subcortical regions. The change in intracerebral node characteristics was different between the APOEε4+ group and the APOEε4- group. Conclusions: Individuals with SCD demonstrate changes in whole-brain network characteristics and intracerebral node characteristics in the structural network. Moreover, differences exist between APOEε4+ and APOEε4- individuals. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA‐33 (miR‐33)‐mediated regulation of this ABCA1–APOE pathway affects phenotypes of an amyloid mouse model. METHODS: We generated mir‐33+/+;APP/PS1 and mir‐33−/−;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR‐33 in microglial migration and amyloid beta (Aβ) phagocytosis. RESULTS: Mir‐33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi‐omics studies suggested miR‐33 regulates the activation and migration of microglia. We confirm that the inhibition of miR‐33 significantly increases microglial migration and Aβ phagocytosis. DISCUSSION: These results suggest that miR‐33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights: Loss of microRNA‐33 (miR‐33) increased ABCA1 protein levels and the lipidation of apolipoprotein E.Loss of miR‐33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis.mRNAs and proteins dysregulated by miR‐33 loss relate to microglia and Alzheimer's disease.Inhibition of miR‐33 increased microglial migration and Aβ phagocytosis in vitro. [ABSTRACT FROM AUTHOR]

Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling. It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them. Apolipoprotein E polymorphism, combined with environmental stresses and/or age-related alterations, influences the risk of developing late-onset Alzheimer's disease. In this review, we discuss our current knowledge of how apolipoprotein E homeostasis, i.e. its synthesis, secretion, degradation, and lipidation, is affected in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. Methods: APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. Results: A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers. Conclusions: We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results. [ABSTRACT FROM AUTHOR]

Heterogeneous behavior of each cell type and their cross-talks in tumor immune microenvironment (TIME) refers to tumor immunological heterogeneity that emerges during tumor progression and represents formidable challenges for effective anti-tumor immune response and promotes drug resistance. To comprehensively elucidate the heterogeneous behavior of individual cell types and their interactions across different stages of tumor development at system level, a computational framework was devised that integrates cell specific data from single-cell RNASeq into networks illustrating interactions among signaling and metabolic response genes within and between cells in TIME. This study identified stage specific novel markers which remodel the cross-talks, thereby facilitating immune stimulation. Particularly, multicellular knockout of metabolic gene APOE (Apolipoprotein E in mast cell, myeloid cell and fibroblast) combined with signaling gene CAV1 (Caveolin1 in endothelial and epithelial cells) resulted in the activation of T-cell mediated signaling pathways. Additionally, this knockout also initiated intervention of cytotoxic gene regulations during tumor immune cell interactions at the early stage of Lung Adenocarcinoma (LUAD). Furthermore, a unique interaction motif from multiple cells emerged significant in regulating the overall immune response at the advanced stage of LUAD. Most significantly, FCER1G (Fc Fragment of IgE Receptor Ig) was identified as the common regulator in activating the anti-tumor immune response at both stages. Predicted markers exhibited significant association with patient overall survival in patient specific dataset. This study uncovers the significance of signaling and metabolic interplay within TIME and discovers important targets to enhance anti-tumor immune response at each stage of tumor development. [ABSTRACT FROM AUTHOR]

Summary Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E (APOE) as the strongest genetic risk for late‐onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid‐β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T‐cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to develop and validate machine learning models (MLMs) to diagnose Alzheimer's disease (AD) using cortical complexity indicated by fractal dimension (FD). Methods: A total of 296 participants with normal cognitive (NC) function and 182 with AD from the AD Neuroimaging Initiative database were randomly divided into training and internal validation cohorts. Then, FDs, demographic characteristics, baseline global cognitive function scales [Montreal Cognitive Assessment (MoCA), Functional Activities Questionnaire (FAQ), Global Deterioration Scale (GDS), Neuropsychiatric Inventory (NPI)], phospho-tau (p-tau 181), amyloidß-42/40, apolipoprotein E (APOE) and polygenic hazard score (PHS) were collected to establish multiple MLMs. Receiver operating characteristic curves were used to evaluate model performance. Participants from our institution (n = 66; 33 with NC and 33 with AD) served as external validation cohorts to validate the MLMs. Decision curve analysis was used to estimate the models' clinical values. Results: The FDs from 30 out of 69 regions showed significant alteration. All MLMs were conducted based on the 30 significantly different FDs. The FD model had good accuracy in predicting AD in three cohorts [area under the receiver operating characteristic (ROC) curve (AUC) = 0.842, 0.808, and 0.803]. There were no statistically significant differences in AUC values between the FD model and the other combined models in the training and internal validation cohorts except MoCA + FD and FAQ + FD models. Among MLMs, the MoCA + FD model showed the best predictive efficiency in three cohorts (AUC = 0.951, 0.931, and 0.955) and had the highest clinical net benefit. Conclusion: The FD model showed favorable diagnostic performance for AD. Among MLMs, the MoCA + FD model can predict AD with the highest efficiency and could be used as a non-invasive diagnostic method. [ABSTRACT FROM AUTHOR]

A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (APOE) as the top lipid-metabolism gene segregating the melanoma MITFhigh/AXLlow proliferative/ferroptosis-resistant from MITFlow/AXLhigh invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITFhigh/AXLlow cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that APOEhigh expression in patients with melanoma is associated with resistance to ferroptosis, regardless of APOE germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and APOEhigh expression as a potential biomarker for poor ferroptosis response in melanoma. [ABSTRACT FROM AUTHOR]

Background: Three common isoforms of the apolipoprotein E (APOE) gene - APOE2, APOE3, and APOE4 - hold varying significance in Alzheimer's Disease (AD) risk. The APOE4 allele is the strongest known genetic risk factor for late-onset Alzheimer's Disease (AD), and its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition and accelerated neurodegeneration. Conversely, APOE2 is associated with reduced AD risk and lower CNS amyloid burden. Recent clinical data have suggested that increased blood-brain barrier (BBB) leakage is commonly observed among AD patients and APOE4 carriers. However, it remains unclear how different APOE isoforms may impact AD-related pathologies at the BBB. Methods: To explore potential impacts of APOE genotypes on BBB properties and BBB interactions with amyloid beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines with different APOE genotypes into both brain microvascular endothelial cell-like cells (BMEC-like cells) and brain pericyte-like cells. We then compared the effect of different APOE isoforms on BBB-related and AD-related phenotypes. Statistical significance was determined via ANOVA with Tukey's post hoc testing as appropriate. Results: Isogenic BMEC-like cells with different APOE genotypes had similar trans-endothelial electrical resistance, tight junction integrity and efflux transporter gene expression. However, recombinant APOE4 protein significantly impeded the "brain-to-blood" amyloid beta 1–40 (Aβ40) transport capabilities of BMEC-like cells, suggesting a role in diminished amyloid clearance. Conversely, APOE2 increased amyloid beta 1–42 (Aβ42) transport in the model. Furthermore, we demonstrated that APOE-mediated amyloid transport by BMEC-like cells is dependent on LRP1 and p-glycoprotein pathways, mirroring in vivo findings. Pericyte-like cells exhibited similar APOE secretion levels across genotypes, yet APOE4 pericyte-like cells showed heightened extracellular amyloid deposition, while APOE2 pericyte-like cells displayed the least amyloid deposition, an observation in line with vascular pathologies in AD patients. Conclusions: While APOE genotype did not directly impact general BMEC or pericyte properties, APOE4 exacerbated amyloid clearance and deposition at the model BBB. Conversely, APOE2 demonstrated a potentially protective role by increasing amyloid transport and decreasing deposition. Our findings highlight that iPSC-derived BBB models can potentially capture amyloid pathologies at the BBB, motivating further development of such in vitro models in AD modeling and drug development. [ABSTRACT FROM AUTHOR]

Visceral obesity (VO), characterized by excess fat around internal organs, is a recognized risk factor for gynecological tumors, including benign uterine leiomyoma (ULM) and malignant uterine leiomyosarcoma (ULS). Despite this association, the shared molecular mechanisms remain underexplored. This study utilizes an integrated bioinformatics approach to elucidate common molecular pathways and identify potential therapeutic targets linking VO, ULM, and ULS. We analyzed gene expression datasets from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) in each condition. We found 101, 145, and 18 DEGs in VO, ULM, and ULS, respectively, with 37 genes overlapping across all three conditions. Functional enrichment analysis revealed that these overlapping DEGs were significantly enriched in pathways related to cell proliferation, immune response, and transcriptional regulation, suggesting shared biological processes. Protein–protein interaction network analysis identified 14 hub genes, of which TOP2A, APOE, and TYMS showed significant differential expression across all three conditions. Drug-gene interaction analysis identified 26 FDA-approved drugs targeting these hub genes, highlighting potential therapeutic opportunities. In conclusion, this study uncovers shared molecular pathways and actionable drug targets across VO, ULM, and ULS. These findings deepen our understanding of disease etiology and offer promising avenues for drug repurposing. Experimental validation is needed to translate these insights into clinical applications and innovative treatments. [ABSTRACT FROM AUTHOR]

Background: Lewy body dementia (LBD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies, which primarily composed of misfolded alpha-synuclein (αS). The development of LBD and APOE4 subtypes is thought to be associated with disorders of lipid metabolism. In this study, we investigated the causal relationship between serum lipids, liposomes and LBD using a two-sample Mendelian randomization (TSMR) method. Methods: A TSMR analysis of genome-wide association study (GWAS) data for 8 serum lipids, 179 lipidomes components, LBD and its subtypes was performed, using inverse variance weighted as the primary outcome. To ensure robustness, the sensitivity analyses including MR Pleiotropy RESidual Sum and Outlier, Cochran's test, leave-one-out method and funnel plots were performed. Results: In this study, we found that low-density lipoprotein cholesterol (LDL-C) (OR=1.45, 95% CI=1.19-1.77, P<0.001) and remnant cholesterol (RC) (OR=2.64, 95% CI=1.64-4.28, P<0.001) had significant positive causal effects on LBD, and RC also had a positive effect on LBD in carriers of the APOE4 gene. The results of lipidome analysis showed that phosphatidylcholine (PC) (O-16:0_20:4) levels (OR=0.86, 95% CI=0.75-0.98, P=0.02) and PC (O-18:1_20:4) levels (OR=0.76, 95% CI=0.65-0.89, P <0.001) had negative causal effects on LBD, whereas phosphatidylinositol (PI) (18:1_20:4) levels had a positive causal effect on LBD (OR=1.19, 95% CI=1.02-1.39, P=0.03). For LBD with APOE4 carriers, high levels of PC (16:1_18:0) and PC (O-18:2_18:1) had a significant positive effect, while high levels of PC (O-16:1_18:0), phosphatidylethanolamine (PE) (O-18:2_18:1), sphingomyelin (SM) (d38:2), and triacylglycerol (TAG) (56:5) significantly reduced the risk. No heterogeneity and horizontal pleiotropy were observed in sensitivity analysis. Conclusion: Elevated LDL-C and RC levels are significant risk factors for LBD, with RC also impacting APOE4-carrying LBD. Glycerophospholipids play a crucial role in the pathogenesis of LBD, but the specific components that play a role differ from those with the APOE4 carries. These findings highlight the importance of lipid metabolism in LBD and APOE4 subtypes. [ABSTRACT FROM AUTHOR]

Motivation We introduce a novel framework BEATRICE to identify putative causal variants from GWAS statistics. Identifying causal variants is challenging due to their sparsity and high correlation in the nearby regions. To account for these challenges, we rely on a hierarchical Bayesian model that imposes a binary concrete prior on the set of causal variants. We derive a variational algorithm for this fine-mapping problem by minimizing the KL divergence between an approximate density and the posterior probability distribution of the causal configurations. Correspondingly, we use a deep neural network as an inference machine to estimate the parameters of our proposal distribution. Our stochastic optimization procedure allows us to sample from the space of causal configurations, which we use to compute the posterior inclusion probabilities and determine credible sets for each causal variant. We conduct a detailed simulation study to quantify the performance of our framework against two state-of-the-art baseline methods across different numbers of causal variants and noise paradigms, as defined by the relative genetic contributions of causal and noncausal variants. Results We demonstrate that BEATRICE achieves uniformly better coverage with comparable power and set sizes, and that the performance gain increases with the number of causal variants. We also show the efficacy BEATRICE in finding causal variants from the GWAS study of Alzheimer's disease. In comparison to the baselines, only BEATRICE can successfully find the APOE ϵ 2 allele, a commonly associated variant of Alzheimer's. Availability and implementation BEATRICE is available for download at https://github.com/sayangsep/Beatrice-Finemapping. [ABSTRACT FROM AUTHOR]

The document "Advances in Neuroinflammation" explores recent research on neuroinflammation and its role in neurological diseases, particularly neurodegenerative diseases. The document highlights the complex nature of neuroinflammation, its double-edged sword effect in the central nervous system, and its involvement in various diseases. Through a series of research and review papers, the authors investigate the mechanisms and potential therapeutic targets related to neuroinflammation in diseases such as Alzheimer's, ALS, glioblastoma, CIDP, insomnia, and multiple sclerosis. The document emphasizes the importance of further research to understand the inflammatory role in disease genesis using diverse tools and technologies. [Extracted from the article]

As a component of circulating lipoproteins, APOE binds to cell surface receptors mediating lipoprotein metabolism and cholesterol transport. A growing body of evidence, including the identification of a broad variety of cellular proteins interacting with APOE, suggests additional independent functions. Investigating cellular localization and protein–protein interactions in cultured human hepatocytes, we aimed to contribute to the elucidation of hitherto unnoted cellular functions of APOE. We observed a strong accumulation of APOE in MAMs, equally evident for the two major isoforms APOE3 and APOE4. Using mass spectrometry proteome analyses, novel and previously noted APOE interactors were identified, including the mitochondrial proteins TOMM40, LONP1 and VDAC1. All three interactors were present in MAM fractions, which we think initially facilitates interactions with APOE. LONP1 is a protease with chaperone activity, which migrated to MAMs in response to ER stress, displaying a reinforced interaction with APOE. We therefore hypothesize that APOE may help in the unfolded protein response (UPR) by acting as a co-chaperone in cooperation with LONP1 at the interface of mitochondria and ER membranes. The interaction of APOE with the integral proteins TOMM40 and VDAC1 may point to the formation of bridging complexes connecting mitochondria with other organelles. [ABSTRACT FROM AUTHOR]

The expression of the APOE3 Christchurch variant (APOE3ch) can provide protection against the progression of Alzheimer's disease (AD) pathology and delays the onset of dementia in individuals with autosomal dominant AD. APOE3ch significantly reduces amyloid-induced tau seeding and spreading in the APP/PS1-21 mouse model. APOE3ch and APOE4ch reduce tau-mediated neurodegeneration in P301S tauopathy mouse models. APOE3ch enhances microglial responses in APP/PS1-21 mice and in tau-seeding/spreading mouse models following AD-tau injection. Protection against tauopathy is linked to competitive receptor-mediated uptake between APOE and tau fibrils via LRP1 and HSPG binding. Over the past 5 years, new protective APOE variants have been identified in patients with AD. The first protective variant against autosomal dominant AD, APOE3ch, has been extensively studied in different mouse models. Emerging findings have uncovered an intriguing relationship between this protective APOE variant and innate immunity in the context of AD pathology. Insights gained from APOE3ch structure and function are encouraging further exploration into the expression of other potential APOE variants. These discoveries may inform novel areas of putative therapeutic development for AD. Recent discoveries of rare variants of human APOE may shed light on novel therapeutic strategies for Alzheimer's disease (AD). Here, we highlight the newly identified protective variant [APOE3 Christchurch (APOE3ch, R136S)] as an example. We summarize human AD and mouse amyloidosis and tauopathy studies from the past 5 years that have been associated with this R136S variant. We also propose a potential mechanism for how this point mutation might lead to protection against AD pathology, from the molecular level, to cells, to mouse models, and potentially, to humans. Lastly, we extend our discussion of the recent insights gained regarding different APOE variants to putative therapeutic approaches in AD. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. Conclusions: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD. [ABSTRACT FROM AUTHOR]

Objective: Apolipoprotein E (APOE) is the most important precursor for the production of steroid hormones and is also involved in regulating the function of steroid hormones, hence playing a significant role in reproductive processes. So, APOE gene expression may be correlated with the implantation process. This study tries to make a better clarification of the correlation between APOE gene polymorphisms and recurrent implantation failure (RIF), where we compared the frequency of APOE polymorphisms in RIF patients, assisted reproductive treatment (ART) success cases and fertile women. Method: In all, 100 women with successful ART who got pregnant (fetal heart rate positive) in their first or second cycle of in vitro fertilization or intracytoplasmic sperm injection, 100 infertile RIF cases, and 100 normal fertile control cases with at least one live birth were included in present study. Following DNA extraction, genotypes were determined through polymerase chain reaction–restriction fragment length polymorphism method using HhaI restriction enzyme. Finally, statistical analysis was performed by chi‐squared (χ2) test in SPSS software (P < 0.05). Results: The RIF group showed significantly higher frequency for E3/E4 genotype (29%) compared with the other two control groups (fertile = 15%, ART success [ART+] = 13%) (P = 0.007). There was also a significantly higher frequency of the E4 allele in the RIF group (14.5%) compared with both of the control groups (fertile = 7.5%, ART+ = 6.5%) (P = 0.018). Conclusion: APOE4 is correlated with recurrent failure in the process of embryo implantation and, accordingly, it may potentially be considered a possible risk factor to the implantation process. The presence of E4 can be proposed as a predictive indicator in determining the results of assisted reproductive techniques. Synopsis: In this study, recurrent implantation failure patients had significantly higher frequency of the APOE‐E4 allele compared with assisted reproductive technology success cases and fertile groups. [ABSTRACT FROM AUTHOR]

Monitoring the progression of Alzheimer's disease (AD) is crucial for mitigating dementia symptoms, alleviating pain, and improving mobility. Traditionally, AD biomarkers like amyloid plaques are predominantly identified in cerebrospinal fluid (CSF) due to their concentrated presence. However, detecting these markers in blood is hindered by the blood–brain barrier (BBB), resulting in lower concentrations. To address this challenge and identify pertinent AD biomarkers—specifically amyloid plaques and apolipoprotein E4 (ApoE4)—in blood plasma, we propose an innovative approach. This involves enhancing a screen-printed carbon electrode (SPCE) with an immobilization matrix comprising gold nanostars (AuNSs) coated with chitosan. Morphological and electrical analyses confirmed superior dispersion and conductivity with 0.5% chitosan, supported by UV–Vis spectroscopy, cyclic voltammetry, and Nyquist plots. Subsequent clinical assays measured electrical responses to quantify amyloid-β 42 (Aβ42) (15.63–1000 pg/mL) and APoE4 levels (0.41 to 40 ng/mL) in human blood plasma samples. Differential pulse voltammetry (DPV) responses exhibited peak currents proportional to biomarker concentrations, demonstrating high linear correlations (0.985 for Aβ42 and 0.919 for APoE4) with minimal error bars. Cross-reactivity tests with mixed solutions of amyloid-β 40 (Aβ40), Aβ42, and ApoE4 indicated minimal interference between biomarkers (<3% variation), further confirming the high specificity of the developed sensor. Validation studies demonstrated a strong concurrence with the gold-standard enzyme-linked immunosorbent assay (ELISA), while interference tests indicated a minimal variation in peak currents. This improved device presents promising potential as a point-of-care system, offering a less invasive, cost-effective, and simplified approach to detecting and tracking the progression of AD. The substantial surface binding area further supports the efficacy of our method, offering a promising avenue for advancing AD diagnostics. [ABSTRACT FROM AUTHOR]

Experiencing decline in both cognition and mobility is associated with a substantially higher dementia risk than cognitive decline only. Metabolites associated with both cognitive and mobility declines may be early predictors of dementia and reveal specific pathways to dementia. We analyzed data from 2450 participants initially free of dementia who had 613 metabolites measured in plasma in 1998–1999 (mean age = 75.2 ± 2.9 years old, 37.8% Black, 50% women) from the Health, Aging and Body Composition study. Dementia diagnosis was determined by race-specific decline in 3MS scores, medication use, and hospital records through 2014. Cognition and mobility were repeatedly measured using 3MS and a 20-m walking test up to 10 years, respectively. We examined metabolite associations with changes in 3MS (n = 2046) and gait speed (n = 2019) using multivariable linear regression adjusted for age, sex, race, and baseline performance and examined metabolite associations with dementia risk using Cox regression. During a mean follow-up of 9.3 years, 534 (21.8%) participants developed dementia. On average, 3MS declined 0.47/year and gait declined 0.04 m/sec/year. After covariate adjustment, 75 metabolites were associated with cognitive decline, and 111 metabolites were associated with gait decline (FDR-adjusted p < 0.05). Twenty-six metabolites were associated with both cognitive and gait declines. Eighteen of 26 metabolites were associated with dementia risk (p < 0.05), notably amino acids, glycerophospholipids (lysoPCs, PCs, PEs), and sphingolipids. Results remained similar after adjusting for cardiovascular disease or apolipoprotein E ɛ4 carrier status. During aging, metabolomic profiles of cognitive decline and mobility decline show distinct and shared signatures. Shared metabolomic profiles suggest that inflammation and deficits in mitochondria and the urea cycle in addition to the central nervous system may play key roles in both cognitive and mobility declines and predict dementia. Future studies are warranted to investigate longitudinal metabolite changes and metabolomic markers with dementia pathologies. [ABSTRACT FROM AUTHOR]

Background: Accelerated biological aging has been verified to be a critical risk factor for a number of age-related diseases, but its role in dementia remained unclear. Whether it modified the effects of genetic factors was also unknown. This study evaluated the associations between accelerated biological aging and dementia and the moderating role of accelerated biological aging in the genetic susceptibility to the disease. Methods: We included 200,731 participants in the UK biobank. Nine clinical blood biomarkers and chronological age were used to calculate Phenotypic age acceleration (PhenoAgeAccel), which is a novel indicator for accelerated biological aging. The associations of PhenoAgeAccel with dementia, both young-onset and late-onset dementia, were assessed by Cox proportional hazard models. Apolipoprotein E (APOE) alleles and polygenic risk scores (PRS) were used to evaluate the genetic risk of dementia. The interactions between genetic susceptibility and biological aging were tested on both multiplicative and additive scales. Results: These findings showed individuals who were in the highest quartile of PhenoAgeAccel had a higher risk with incidence of dementia compared to individuals in the lowest quartile of PhenoAgeAccel (HR: 1.145 (95% CI: 1.050, 1.249)). Individuals with biologically older had a higher risk of dementia than individuals with biologically younger (HR: 1.069 (95% CI: 1.004, 1.138)). Furthermore, compared to individuals with biologically younger and low APOE ε4-related genetic risk, individuals with biologically younger and high APOE ε4-related genetic risk (HR:3.048 (95% CI: 2.811, 3.305)) had a higher risk of dementia than individuals with biologically older and high APOE ε4-related genetic risk (HR: 2.765 (95% CI: 2.523, 3.029)). Meanwhile, referring to low dementia PRS and biologically younger, the risk of dementia increased by 72.7% (HR: 1.727 (95% CI: 1.538, 1.939) in the biologically younger and high PRS group and 58.7% (HR: 1.587 (95% CI: 1.404, 1.793) in the biologically older and high PRS group, respectively. The negative interactions between PhenoAgeAccel with APOE ε4 and PRS were also tested on the additive scale. Conclusions: Accelerated biological aging could bring the extra risk of dementia but attenuate the effects of genetic risk on dementia. These findings provide insights for precise prevention and intervention of dementia. [ABSTRACT FROM AUTHOR]

Background: Impulse control disorders (ICDs) are an increasingly recognized complication in Parkinson disease (PD). The pathogenesis of ICDs is currently unclear. Few genetic studies have been conducted in this area. Objective: We aimed to ascertain the correlation between APOE and ICDs, and identify clinical predictors of ICDs in PD. Methods: This study included 287 PD patients from the Parkinson's Progression Markers Initiative. They were followed up to investigate the progression of ICDs over a period of 5 years. The cumulative incidence of ICDs and potential risk factors were evaluated using Kaplan-Meier and Cox regression analyses. Results: 44.3% (31/70) patients with APOE ɛ4 and 32.3% (70/217) patients without APOE ɛ4 developed ICDs during the five-year follow up period. There were significant differences between the PD with and without ICDs development group in age, MSEADLG score, ESS score, GDS score, and STAI score at baseline. In multivariable Cox regression analysis, APOE ε4 (HR = 1.450, p = 0.048) and STAI score (HR = 1.017, p = 0.001) were predictors of the development of ICDs. Patients with APOE ɛ4 group showed significantly lower CSF Aβ42 and CSF α-syn level than patients without APOE ɛ4 group at baseline. In patients with APOE ɛ4 group, the "low α-syn level" group and the "low ptau/tau ratio" group had a significantly higher incidence of ICDs, respectively. Conclusions: This study provides important insights into the potential role of the APOE gene in the development of ICDs in PD. Further studies are needed to confirm our findings and to investigate the underlying mechanisms in more detail. [ABSTRACT FROM AUTHOR]

Alport syndrome (AS) is one of the most common inherited kidney disorders, involving pathogenic variants of COL4A3, COL4A4 and COL4A5 genes that lead to disruption of the normal structure of collagen IV protein through improper chain or heterotrimer folding or degradation of heterotrimer components. Lipoprotein glomerulopathy (LPG) is an autosomal dominant disease involving APOE gene mutations disturbing lipoprotein metabolism. We report the first case with both AS and LPG in an 11‐year‐old girl. The patient presented with blepharedema, and decreased vision. Laboratory examinations showed hematemesis, proteinuria, hypoproteinemia, hyperlipidemia and progressive renal failure. Renal biopsy showed the changes of LPG and AS. Whole‐exome sequencing (WES) identified two pathogenic variants, c.127C > T in exon 3 of APOE gene, and c.930 + 1G > A in exon 15 of COL4A4 gene. We emphasize the importance of early completion of renal biopsy and WES for early diagnosis of LPG and AS. [ABSTRACT FROM AUTHOR]

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer's disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke. Methods: Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10-5 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts. Results: In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found. Discussion: In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias. [ABSTRACT FROM AUTHOR]

Both the ε4 variant of the apolipoprotein E (APOE) gene and hearing loss are well-known risk factors for Alzheimer's disease. However, previous studies have produced inconsistent findings regarding the association between APOE genotypes and hearing levels, necessitating further investigation. The aim of this study was to investigate the relationship between APOE genotypes and hearing levels. This retrospective study analyzed clinical data from a clinical data warehouse of seven affiliated Catholic Medical Center hospitals. The study included 1,162 participants with records of APOE genotypes, audiometric tests, and cognitive function tests. In Generalized linear mixed model analysis, ε4 carriers exhibited lower pure tone audiometry thresholds with an estimate of -0.353 (SE = 0.126, p = 0.005). However, the interaction term for age and APOE ε4 had a coefficient of 0.577 (SE = 0.214 p = 0.006), suggesting that the APOE ε4 gene may accelerate hearing deterioration with age. Subgroup analysis based on an age cut-off of 75 revealed that ε4 carriers had better hearing at younger ages, but showed no significant difference at older ages. These results indicate that the ε4 allele may have a biphasic effect on hearing levels depending on age. [ABSTRACT FROM AUTHOR]

Objective: Apolipoprotein E (APOE) gene polymorphisms were associated with coronary atherosclerosis and hypertension. However, the relationship between APOE polymorphisms and coronary atherosclerosis susceptibility in hypertensive patients is unclear. The aim of this study was to assess the relationship. Methods: A total of 1713 patients with hypertension who were admitted to Meizhou People's Hospital from November 2019 to August 2023 were retrospectively analyzed, including 848 patients with coronary atherosclerosis and 865 patients without coronary atherosclerosis. The rs429358 and rs7412 polymorphisms of APOE were genotyped, and relationship between APOE polymorphisms and the risk of coronary atherosclerosis in hypertensive patients were analyzed. Results: There were 10 (0.6%), 193 (11.3%), 30 (1.8%), 1234 (72.0%), 233 (13.6%), and 13 (0.8%) individuals with APOE ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4 genotype, respectively. The frequency of APOE ɛ3/ɛ4 was higher (16.4% vs. 10.9%, p = 0.001) in the patients with coronary atherosclerosis than controls. Logistic analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (24.0 kg/m2 vs. 18.5–23.9 kg/m2, odds ratio (OR): 1.361, 95% confidence interval (CI): 1.112–1.666, p = 0.003), advanced age (≥ 65/<65, OR:1.303, 95% CI: 1.060–1.602, p = 0.012), history of smoking (OR: 1.830, 95% CI: 1.379–2.428, p < 0.001), diabetes mellitus (OR: 1.380, 95% CI: 1.119–1.702, p = 0.003), hyperlipidemia (OR: 1.773, 95% CI: 1.392–2.258, p < 0.001), and APOE ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 1.514, 95% CI: 1.133–2.024, p = 0.005) were associated with coronary atherosclerosis in hypertensive patients. Conclusions: Overweight (BMI ≥ 24.0 kg/m2), advanced age, history of smoking, diabetes mellitus, and APOE ɛ3/ɛ4 genotype were independent risk factors for coronary atherosclerosis in hypertensive patients. [ABSTRACT FROM AUTHOR]

We aimed to develop and validate a protein risk score for predicting Alzheimer's disease (AD) and compare its performance with a validated clinical risk model (Cognitive Health and Dementia Risk Index for AD [CogDrisk‐AD]) and apolipoprotein E (APOE) genotypes. The development cohort, consisting of 35,547 participants from England in the UK Biobank, was randomly divided into a 7:3 training–testing ratio. The validation cohort included 4667 participants from Scotland and Wales in the UK Biobank. In the training set, an AD protein risk score was constructed using 31 proteins out of 2911 proteins. In the testing set, the AD protein risk score had a C‐index of 0.867 (95% CI, 0.828, 0.906) for AD prediction, followed by CogDrisk‐AD risk factors (C‐index, 0.856; 95% CI, 0.823, 0.889), and APOE genotypes (C‐index, 0.705; 95% CI, 0.660, 0.750). Adding the AD protein risk score to CogDrisk‐AD risk factors (C‐index increase, 0.050; 95% CI, 0.008, 0.093) significantly improved the predictive performance for AD. However, adding CogDrisk‐AD risk factors (C‐index increase, 0.040; 95% CI, −0.007, 0.086) or APOE genotypes (C‐index increase, 0.000; 95% CI, −0.054, 0.055) to the AD protein risk score did not significantly improve the predictive performance for AD. The top 10 proteins with the highest coefficients in the AD protein risk score contributed most of the predictive power for AD risk. These results were verified in the external validation cohort. EGFR, GFAP, and CHGA were identified as key proteins within the protein network. Our result suggests that the AD protein risk score demonstrated a good predictive performance for AD risk. [ABSTRACT FROM AUTHOR]

Background: There is initial evidence suggesting that biomarker neurogranin (Ng) may distinguish Alzheimer's disease (AD) from other neurodegenerative diseases. Therefore, we assessed (a) the discriminant ability of cerebrospinal fluid (CSF) Ng levels to distinguish between AD and frontotemporal lobar degeneration (FTLD) pathology and between different stages within the same disease, (b) the relationship between Ng levels and cognitive performance in both AD and FTLD pathology, and (c) whether CSF Ng levels vary by apolipoprotein E (APOE) polymorphism in the AD continuum. Methods: Participants with subjective cognitive decline (SCD) (n = 33), amnestic mild cognitive impairment (aMCI) due to AD (n = 109), AD dementia (n = 67), MCI due to FTLD (n = 25), and FTLD dementia (n = 29) were recruited from the Czech Brain Aging Study. One-way analysis of covariance (ANCOVA) assessed Ng levels in diagnostic subgroups. Linear regressions evaluated the relationship between CSF Ng levels, memory scores, and APOE polymorphism. Results: Ng levels were higher in aMCI-AD patients compared to MCI-FTLD (F[1, 134] = 15.16, p <.001), and in AD-dementia compared to FTLD-dementia (F[1, 96] = 4.60, p =.029). Additionally, Ng levels were higher in FTLD-dementia patients compared to MCI-FTLD (F[1, 54]= 4.35, p =.034), lower in SCD participants compared to aMCI-AD (F[1, 142] = 10.72, p =.001) and AD-dementia (F[1, 100] = 20.90, p <.001), and did not differ between SCD participants and MCI-FTLD (F[1, 58]= 1.02, p =.491) or FTLD-dementia (F[1, 62]= 2.27, p =.051). The main effect of diagnosis across the diagnostic subgroups on Aβ1−42/Ng ratio was significant too (F[4, 263]=, p <.001). We found a non-significant association between Ng levels and memory scores overall (β=-0.25, p =.154) or in AD diagnostic subgroups, and non-significant differences in this association between overall AD APOE ε4 carriers and non-carriers (β=-0.32, p =.358). Conclusions: In this first study to-date to assess MCI and dementia due to AD or FTLD within one study, elevated CSF Ng appears to be an early biomarker of AD-related impairment, but its role as a biomarker appears to diminish after dementia diagnosis, whereby dementia-related underlying processes in AD and FTLD may begin to merge. The Aβ1−42/Ng ratio discriminated AD from FTLD patients better than Ng alone. CSF Ng levels were not related to memory in AD or FTLD, suggesting that Ng may be a marker of the biological signs of disease state rather than cognitive deficits. [ABSTRACT FROM AUTHOR]

The strongest genetic risk factor for late‐onset Alzheimer's disease (AD) is allelic variation of the APOE gene, with the following risk structure: ε4 > ε3 > ε2. The biochemical basis for this risk profile is unclear. Here, we reveal a new role for the APOE gene product, apolipoprotein E (ApoE) in regulating cellular copper homeostasis, which is perturbed in the AD brain. Exposure of ApoE target replacement (TR) astrocytes (immortalised astrocytes from APOE knock‐in mice) to elevated copper concentrations resulted in exacerbated copper accumulation in ApoE4‐ compared to ApoE2‐ and ApoE3‐TR astrocytes. This effect was also observed in SH‐SY5Y neuroblastoma cells treated with conditioned medium from ApoE4‐TR astrocytes. Increased intracellular copper levels in the presence of ApoE4 may be explained by reduced levels and delayed trafficking of the copper transport protein, copper‐transporting ATPase 1 (ATP7A/Atp7a), potentially leading to impaired cellular copper export. This new role for ApoE in copper regulation lends further biochemical insight into how APOE genotype confers risk for AD and reveals a potential contribution of ApoE4 to the copper dysregulation that is a characteristic pathological feature of the AD brain. [ABSTRACT FROM AUTHOR]

APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex‐ and age‐dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC–MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (>5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7–10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3‐fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4‐induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4‐induced alterations may modulate the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Background: This study examined the impact of apolipoprotein ɛ4 (APOEɛ4) allele frequency and sex on the phenotype of Alzheimer's disease (AD). Methods: This post hoc study evaluated the baseline characteristics, cerebrospinal fluid (CSF) and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50–74 years with CSF-biomarker-confirmed mild cognitive impairment or mild dementia due to AD from clinical trial NCT03186989. Results: A phenotypic spectrum was observed from a predominant amyloid and limbic–amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology was inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest associations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers. Conclusions: These data support the hypothesis that functional glial activation is influenced by apoE isoform and sex and might explain much of the biological and clinical heterogeneity in early clinical AD in those aged 50–74 years. Conclusions are limited because of the retrospective nature and small sample size. Trial Registration: Clinical Trial NCT03186989. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a leading cause of dementia, and it is significantly influenced by the apolipoprotein E4 (APOE4) gene and gender. This study aimed to use machine learning (ML) algorithms to predict brain age and assess AD risk by considering the effects of the APOE4 genotype and gender. Methods: We collected brain volumetric MRI data and medical records from 1100 cognitively unimpaired individuals and 602 patients with AD. We applied three ML regression models—XGBoost, random forest (RF), and linear regression (LR)—to predict brain age. Additionally, we introduced two novel metrics, brain age difference (BAD) and integrated difference (ID), to evaluate the models' performances and analyze the influences of the APOE4 genotype and gender on brain aging. Results: Patients with AD displayed significantly older brain ages compared to their chronological ages, with BADs ranging from 6.5 to 10 years. The RF model outperformed both XGBoost and LR in terms of accuracy, delivering higher ID values and more precise predictions. Comparing the APOE4 carriers with noncarriers, the models showed enhanced ID values and consistent brain age predictions, improving the overall performance. Gender-specific analyses indicated slight enhancements, with the models performing equally well for both genders. Conclusions: This study demonstrates that robust ML models for brain age prediction can play a crucial role in the early detection of AD risk through MRI brain structural imaging. The significant impact of the APOE4 genotype on brain aging and AD risk is also emphasized. These findings highlight the potential of ML models in assessing AD risk and suggest that utilizing AI for AD identification could enable earlier preventative interventions. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis with a systematic review was undertaken to assess the association between APOE allelic genotypes and the risk of Alzheimer's disease (AD) in the Italian population. Methods: The Web of Science, PubMed, and Scopus databases were searched until 15 November 2023. The odds ratio (OR) with a 95% confidence interval (CI) was calculated using fixed and random effect models, depending on the I2 statistic value. The systematic review and meta-analysis were conducted in agreement with the PRISMA guideline and registered with PROSPERO (CRD42023492580). Results: Our meta-analysis based on 15 studies revealed a higher risk of AD among Italian individuals carrying the APOE ε4 allele (OR = 3.60, 95% CI [2.90–4.47], p < 0.0001). The association of AD genotype APOE ε2ε4 (OR = 1.36, 95% CI [0.76–2.41], p = 0.29) was not statistically significant, while APOE ε3ε4 (OR = 3.43, 95% CI [2.95–3.99], p < 0.0001) has a high risk of AD development; the risk is more notably in the APOE ε4ε4 genotype (OR = 7.08, 95% CI [4.22–11.86], p < 0.0001). The APOE ε2 allele has a protective effect (APOE ε2 (OR = 0.47, 95% CI [0.29–0.74], p = 0.0013)), and similar results were achieved by APOE ε3 (OR  =  0.49, 95% CI [0.37–0.65], p < 0.0001). Subgroup analysis of three areas of Italy (southern, northern, and center) revealed that that APOE ε4 allele was a risk factor with a higher OR in northern Italy (OR 4.22; 95% CI [3.46–5.16], p < 0.0001) compared to southern and center Italy (OR 3.02; 95% CI [2.28–4.01], p < 0.0001 and OR 3.97; 95% CI [1.37–11.56], p < 0.0001, respectively). As well, APOE ε4ε4 genotype carriers had a significantly higher OR in northern Italy (OR 9.69; 95% CI [4.94–18.99], p < 0.0001) compared to in southern and center Italy (OR 4.38; 95% CI [1.54–12.47], p < 0.0001 and OR 3.59; 95% CI [0.87–14.86], p < 0.0001, respectively). Conclusions: This systematic review with a meta-analysis of the Italian population on APOE alleles, genotyping, and AD incidence, highlights that individuals harboring APOE ε4 have a higher risk of developing AD compared to those with other alleles. It also supports the protective effect of the APOE ε2 allele against the progress of AD. The qualitative analysis on the complex genetic interactions influencing Alzheimer risk emphasizes the need for further research on genetic and environmental factors for effective prevention strategies. [ABSTRACT FROM AUTHOR]

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APPNL-F/NL-F knock-in (KI) mice bearing humanized ApoE3 or ApoE4 (APP;E3F and APP;E4F). As travel to a specialized facility was required for irradiation, both traveled sham-irradiated C57BL/6J WT and KI mice and non-traveled (NT) KI mice acted as controls for potential effects of travel. Mice underwent four behavioral tests at 20 months of age and were euthanized for pathological and biochemical analyses 1 month later. Fecal samples were collected pre- and post-irradiation at four different time points. GCRsim seemed to impair memory in male APP;E3F mice compared to their sham counterparts. Travel tended to improve cognition in male APP;E3F mice and lowered total Aβ in female and male APP;E3F mice compared to their non-traveled counterparts. Sham-irradiated male APP;E4F mice accumulated more fibrillar amyloid than their APP;E3F counterparts. Radiation exposure had only modest effects on behavior and brain changes, but travel-, sex-, and genotype-specific effects were seen. Irradiated mice had immediate and long-term differences in their gut bacterial composition that correlated to Alzheimer's disease phenotypes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, the most prevalent form of dementia, imposes a substantial societal burden. The persistent inadequacy of disease-modifying drugs targeting amyloid plaques and neurofibrillary tangles suggests the contribution of alternative pathogenic mechanisms. A frequently overlooked aspect is cerebrovascular dysfunction, which may manifest early in the progression of Alzheimer's disease pathology. Mounting evidence underscores the pivotal role of the apolipoprotein E gene, particularly the apolipoprotein ε4 allele as the strongest genetic risk factor for late-onset Alzheimer's disease, in the cerebrovascular pathology associated with Alzheimer's disease. In this review, we examine the evidence elucidating the cerebrovascular impact of both central and peripheral apolipoprotein E on the pathogenesis of Alzheimer's disease. We present a novel three-hit hypothesis, outlining potential mechanisms that shed light on the intricate relationship among different pathogenic events. Finally, we discuss prospective therapeutics targeting the cerebrovascular pathology associated with apolipoprotein E and explore their implications for future research endeavours. [ABSTRACT FROM AUTHOR]

Background: Systemic infections are associated with the development of AD, especially in individuals carrying the APOE4 genotype. However, the detailed mechanism through which APOE4 affects microglia inflammatory response remains unclear. Methods: We obtained human snRNA‐seq data from the Synapse AD Knowledge Portal and assessed the DEGs between APOE3 and APOE4 isoforms in microglia. To verify the interaction between ApoE and infectious products, we used ApoE to stimulate in vitro and in vivo models in the presence or absence of LPS (or ATP). The NLRP3 gene knockout experiment was performed to demonstrate whether the APOE‐NLRP3 axis was indispensable for microglia to regulate inflammation and mitochondrial autophagy. Results were evaluated by biochemical analyses and fluorescence imaging. Results: Compared with APOE3, up‐regulated genes in APOE4 gene carriers were involved in pro‐inflammatory responses. ApoE4‐stimulation significantly increased the levels of NLRP3 inflammasomes and ROS in microglia. Moreover, compared with ApoE4 alone, the co‐incubation of ApoE4 with LPS (or ATP) markedly promoted pyroptosis. Both NF‐κB activation and mitochondrial autophagy dysfunction were contributed by the increased level of NLRP3 inflammasomes induced by ApoE4. Furthermore, the pathological impairment induced by ApoE4 could be reversed by NLRP3 KO. Conclusions: Our study highlights the importance of NLRP3 inflammasomes in linking ApoE4 with microglia innate immune function. These findings not only provide a molecular basis for APOE4‐mediated neuroinflammatory but also reveal the potential reason for the increased risk of AD in APOE4 gene carriers after contracting infectious diseases. [ABSTRACT FROM AUTHOR]

This work is motivated by a gap in the functional data analysis literature, particularly in the context of neuroimaging, regarding the ability of functional models to robustly accommodate intra‐observation dependence. In response, we propose an M‐estimator based on generalized empirical likelihood for the varying‐coefficient model with a functional response. We develop statistical inference procedures, simultaneous confidence regions, and a global general linear hypothesis test for the model's functional coefficient. Our theoretical results establish the weak convergence of the log‐likelihood ratio process, a nonparametric version of Wilks' theorem for the log‐likelihood ratio, and asymptotic properties of the proposed estimator. Through a simulation study, we show that the proposed confidence sets have close‐to‐nominal coverage probabilities. In a real‐world application to a neuroimaging dataset, we show that mini‐mental state examination score and apolipoprotein E genotype have significant associations with fractional anisotropy, while associations with gender and age are only present at high quantile levels. [ABSTRACT FROM AUTHOR]