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Cadmium (Cd) exposure is associated with increased Alzheimer's disease (AD) risks. The human Apolipoprotein E (

The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.

Background: APOE ɛ4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps 10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.

RationaleThe blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). Focused ultrasound applied together with microbubbles (FUS+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS+MBis safe, however the effects of FUS+MBon human BBB cells, especially in the context of AD, remain sparsely investigated.MethodsHere we generated BBB cells (induced brain endothelial cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We then developed a human sporadic AD BBB cell platform to investigate the effects of FUS+MBon BBB cells and screen for the delivery of two potentially therapeutic AD antibodies.ResultsWe utilized this robust and reproducible human BBB model to demonstrate increased delivery of therapeutic AD antibodies across the BBB following FUS+MBtreatment, including an analogue of Aducanumab (AduhelmTM; anti-amyloid-β) and a novel anti-Tau antibody RNF5. Our results also demonstrate the safety of FUS+MBindicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within the first 24 h post FUS+MB. Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS+MB-mediated drug delivery screening, with potentially higher translational utility.ConclusionOur results demonstrate an important translatable patient BBB cell model for identifying FUS+MB-deliverable drugs and screening for cell- and patient-specific effects of FUS+MB, accelerating the use of FUS+MBas a therapeutic modality in AD.One Sentence SummaryFocused ultrasound increases thein vitrodelivery of therapeutic antibodies Aducanumab and anti-Tau in a sporadic Alzheimer’s disease patient-derived blood-brain barrier cell model.

Summary The apolipoprotein E4 (APOE4) variant is the strongest genetic risk factor for Alzheimer disease (AD), while the APOE2 allele is protective. A major question is how different APOE genotypes affect the physiology of astrocytes, the main APOE-producing brain cells. Here, we differentiated human APOE-isogenic induced pluripotent stem cells (iPSCs) (APOE4, E3, E2, and APOE knockout [APOE-KO]) to functional “iAstrocytes”. Mass-spectrometry-based proteomic analysis showed genotype-dependent reductions of cholesterol and lipid metabolic and biosynthetic pathways (reduction: APOE4 > E3 > E2). Cholesterol efflux and biosynthesis were reduced in APOE4 iAstrocytes, while subcellular localization of cholesterol in lysosomes was elevated. An increase in immunoregulatory proteomic pathways (APOE4 > E3 > E2) was accompanied by elevated cytokine release in APOE4 cells (APOE4 > E3 > E2 > KO). Activation of iAstrocytes exacerbated proteomic changes and cytokine secretion mostly in APOE4 iAstrocytes, while APOE2 and APOE-KO iAstrocytes were least affected. Taken together, APOE4 iAstrocytes reveal a disease-relevant phenotype, causing dysregulated cholesterol/lipid homeostasis, increased inflammatory signaling, and reduced β-amyloid uptake, while APOE2 iAstrocytes show opposing effects., Highlights • Human astrocytes show strong proteomic differences depending on their APOE genotype • Aβ uptake is highest in APOE-KO and lowest in APOE4 astrocytes (KO > E2 > E3 > E4) • APOE4 astrocytes show exacerbated pro-inflammatory reactions (APOE4 > E3 > E2 > KO) • Cholesterol synthesis and efflux are reduced in APOE4 astrocytes, In this article, Tackenberg and colleagues show APOE genotype-dependent differences in the proteomic profile of APOE-isogenic iPSC-derived human astrocytes. They provide evidence for a pro-inflammatory state of APOE4 iAstrocytes, while APOE2 and APOE-KO iAstrocytes show reduced inflammatory signaling. They further show the APOE genotype-dependent regulation of β-amyloid uptake capacity and cholesterol/lipid homeostasis and a differential reaction to inflammatory stimuli.

Age, apolipoprotein E (apoE) isoform, sex, and diet can independently affect the risk for the development of Alzheimer’s disease (AD). Additionally, synergy between some of these risk factors have been observed. However, the relation between the latter three risk factors has not been investigated. Central nervous system (CNS) insulin resistance is commonly involved in each of these risk factors. CNS insulin is primarily derived from the periphery in which insulin must be transported across the blood–brain barrier (BBB). Additionally, insulin can bind the brain endothelial cell to affect intracellular signaling. Therefore, we hypothesized CNS access to insulin could be affected by the combination of apoE isoform, sex, and diet. We analyzed insulin BBB pharmacokinetics in aged apoE targeted replacement (E3 and E4) male and female mice on a low-fat and high-fat diet. There were differences within males and females due to apoE genotype and diet in insulin interactions at the BBB. These sex-, diet-, and apoE isoform-dependent differences could contribute to the cognitive changes observed due to altered CNS insulin signaling.

[Objective] The purpose of this study was to examine the levels of cerebrospinal fluid (CSF) apolipoprotein E (apoE) species in Alzheimer’s disease (AD) patients., [Methods] We analyzed two CSF cohorts of AD and control individuals expressing different APOE genotypes. Moreover, CSF samples from the TgF344-AD rat model were included. Samples were run in native- and SDS-PAGE under reducing or non-reducing conditions (with or without β-mercaptoethanol). Immunoprecipitation combined with mass spectrometry or western blotting analyses served to assess the identity of apoE complexes., [Results] In TgF344-AD rats expressing a unique apoE variant resembling human apoE4, a ~35-kDa apoE monomer was identified, increasing at 16.5 months compared with wild-types. In humans, apoE isoforms form disulfide-linked dimers in CSF, except apoE4, which lacks a cysteine residue. Thus, controls showed a decrease in the apoE dimer/monomer quotient in the APOE ε3/ε4 group compared with ε3/ε3 by native electrophoresis. A major contribution of dimers was found in APOE ε3/ε4 AD cases, and, unexpectedly, dimers were also found in ε4/ε4 AD cases. Under reducing conditions, two apoE monomeric glycoforms at 36 kDa and at 34 kDa were found in all human samples. In AD patients, the amount of the 34-kDa species increased, while the 36-kDa/34-kDa quotient was lower compared with controls. Interestingly, under reducing conditions, a ~100-kDa apoE complex, the identity of which was confirmed by mass spectrometry, also appeared in human AD individuals across all APOE genotypes, suggesting the occurrence of aberrantly resistant apoE aggregates. A second independent cohort of CSF samples validated these results., [Conclusion] These results indicate that despite the increase in total apoE content the apoE protein is altered in AD CSF, suggesting that function may be compromised., This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS; PI15/00665 and PI19-01359, co-funded by the Fondo Europeo de Desarrollo Regional, FEDER “Investing in your future”), from the CIBERNED (Instituto de Salud Carlos III, Spain) and from the Direcció General de Ciència I Investigació, Generalitat Valenciana (AICO/2021/308). We also acknowledge financial support from the Spanish Ministerio de Economía y Competitividad, through the “Severo Ochoa” Programme for Centres of Excellence in R&D (SEV-2017-0723). MPL is supported by a BEFPI fellowship from the Generalitat Valenciana. This study was also supported by the FIS, Contratos para la intensificación de la actividad investigadora en el SNS from Instituto de Salud Carlos III (PI14/01126, PI17/01019, PI20/01473, and INT16/00171 to JF; PI18/00435 to DA; PI14/1561, PI17/01896, and PI20/1330 to AL). This work was also supported by the CIBERNED program (Program 1, Alzheimer Disease to AL and SIGNAL study, www.signalstudy.es), the National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, and R01AG061566 to JF), and Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (SLT002/16/00408 to AL). This work was also supported by Generalitat de Catalunya (SLT006/17/00119 to JF and SLT006/17/00125 to DA). This study was also supported by the Spanish Ministry of Science, Innovation and Universities MICINN/FEDER (PID2019-107738RB-I00, to FA, a fellowship to ISD and the “Maria Maeztu Unit of Excellence Program”) and Instituto de Salud Carlos III (PI18/00893 to GS, co-funded by ERDF, “A way to make Europe”). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532); the European Research Council (#681712); the Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C); the Olav Thon Foundation; the Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; Hjärnfonden, Sweden (#FO2019-0228); the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE); the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694); and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); the Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236); the National Institute of Health (NIH), USA (grant #1R01AG068398-01); and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495).

The association of the APOE4 (vs APOE3) isoform with an increased risk of Alzheimer’s Disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elu-cidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking apolipoprotein isoform to disease aetiology. APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several alterations in pathways of lipid homeostasis in the brains of mice expressing the human APOE4 versus APOE3 isoform. Carriers of APOE4 had deficient cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing poly-unsaturated fatty acids and an overall eleva-tion in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related with increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of AP-OE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.

Background: Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T-tests with Bonferroni correction (significance = p

INTRODUCTION Despite advances, understanding the protective role of the apolipoprotein E (APOE) e2 allele in Alzheimer's disease (AD) remains elusive. METHODS We examined associations of variants comprised of the TOMM40 rs8106922 and APOE rs405509, rs440446, and e2-encoding rs7412 polymorphisms with AD in a sample of 2862 AD-affected and 169,516 AD-unaffected non-carriers of the e4 allele. RESULTS Association of the e2/e3 heterozygote of men with AD is 38% (P = 1.65 × 10-2 ) more beneficial when it is accompanied by rs8106922 major allele homozygote and rs405509 and rs440446 heterozygotes than by rs8106922 heterozygote and rs405509 and rs440446 major allele homozygotes. No difference in the beneficial associations of these two most common e2/e3-bearing variants with AD was identified in women. The role of e2/e3 heterozygote may be affected by different immunomodulation functions of rs8106922, rs405509, and rs440446 variants in a sex-specific manner. DISCUSSION Combination of TOMM40 and APOE variants defines a more homogeneous AD-protective e2/e3-bearing profile in men.

Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17–1.42, p

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

Body mass index (BMI) has been suggested to play an important role in the relationship between the

A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.

White matter degradation in the frontal lobe is one of the earliest detectable changes in aging and Alzheimer disease. The ε4 allele of apolipoprotein E (APOE4) is strongly associated with such myelin pathology but the underlying cellular mechanisms remain obscure. We hypothesized that, as a lipid transporter, APOE4 directly triggers pathology in the cholesterol-rich myelin sheath independent of AD pathology. To test this, we performed immunohistochemistry on brain tissues from healthy controls, sporadic, and familial Alzheimer disease subjects. While myelin basic protein expression was largely unchanged, in frontal cortex the number of oligodendrocytes (OLs) was significantly reduced in APOE4 brains independent of their Braak stage or NIA-RI criteria. This high vulnerability of OLs was confirmed in humanized APOE3 or APOE4 transgenic mice. A gradual decline of OL numbers was found in the aging brain without associated neuronal loss. Importantly, the application of lipidated human APOE4, but not APOE3, proteins significantly reduced the formation of myelinating OL in primary cell culture derived from Apoe-knockout mice, especially in cholesterol-depleted conditions. Our findings suggest that the disruption of myelination in APOE4 carriers may represent a direct OL pathology, rather than an indirect consequence of amyloid plaque formation or neuronal loss.

Recent studies have revealed that the inflammatory

Optical neuritis (ON), otherwise known as optical nerve damage, is a term used to describe various environmental and body conditions that lead to optic nerve dysfunction. Neurologists are well aware of conditions that cause optic neuropathy, such as trauma, infections, malnutrition, and various toxins. As optic neuritis is a multifactorial demyelinating or infectious process, genetic predisposition may also influence the progression of optic neuritis. This study aimed to evaluate the association of ON (with and without multiple sclerosis) with

The impact of Apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells (hiPSCs), post-mortem brain and APOE targeted replacement (APOE-TR) mice. Population and isogenic models demonstrate that APOE4 local haplotype rather than a single risk allele contributes to risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60–80 years) diagnosed with subjective cognitive decline and APOE ɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer’s disease should be further evaluated.

Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (–0.31 points, 95% CI: –0.57, –0.05) and delayed (–0.37 points, 95% CI: –0.64, –0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. Conclusion: The APOE ɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ɛ2 allele was not significantly associated with any of the cognitive test scores.

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.

Introduction: The APOE ϵ4 allele predisposes to high cholesterol and increases the risk for lifestyle-related diseases such as Alzheimer's disease and cardiovascular diseases (CVDs). The aim of this study was to analyse interrelationships of APOE genotypes with lipid metabolism and lifestyle factors in middle-aged Finns among whom the CVD risk factors are common. Methods: Participants (n = 211) were analysed for APOE ϵ genotypes, physiological parameters, and health- and diet-related plasma markers. Lifestyle choices were determined by a questionnaire. Results: APOE genotypes ϵ3/ϵ4 and ϵ4/ϵ4 (ϵ4 group) represented 34.1% of the participants. Genotype ϵ3/ϵ3 (ϵ3 group) frequency was 54.5%. Carriers of ϵ2 (ϵ2 group; ϵ2/ϵ2, ϵ2/ϵ3 and ϵ2/ϵ4) represented 11.4%; 1.9% were of the genotype ϵ2/ϵ4. LDL and total cholesterol levels were lower (p < 0.05) in the ϵ2 carriers than in the ϵ3 or ϵ4 groups, while the ϵ3 and ϵ4 groups did not differ. Proportions of plasma saturated fatty acids (SFAs) were higher (p < 0.01), and omega-6 fatty acids lower (p = 0.01) in the ϵ2 carriers compared with the ϵ4 group. The ϵ2 carriers had a higher (p < 0.05) percentage of 22:4n-6 and 22:5n-6 and a lower (p < 0.05) percentage of 24:5n-3 and 24:6n-3 than individuals without the ϵ2 allele. Conclusions: The plasma fatty-acid profiles in the ϵ2 group were characterized by higher SFA and lower omega-6 fatty-acid proportions. Their lower cholesterol values indicated a lower risk for CVD compared with the ϵ4 group. A novel finding was that the ϵ2 carriers had different proportions of 22:4n-6, 22:5n-6, 24:5n-3, and 24:6n-3 than individuals without the ϵ2 allele. The significance of the differences in fatty-acid composition remains to be studied. publishedVersion

Apolipoprotein E (APOE) gene encodes three protein isoforms (APOEε-22/ε-33/ε-44), which governs the transportation and metabolism of lipoproteins differently. While abnormalities in lipid and lipoprotein metabolism have been identified as risk factors for type 2 diabetes mellitus (T2DM). APOE gene polymorphisms might be correlated with increased risk of T2DM. Therefore, we presented an iPSC line harboring an APOE-ε3/ε3 alleles, a male donor suffering from T2DM combined with Hypertension. The derived iPSCs showed pluripotency, the capacity to differentiate into three germ layers, and normal karyotypes. Collectively, the present study provides a useful resource to reveal the associated mechanism of APOE isoform and T2DM.

Alzheimer’s disease (AD) is fast becoming one of the most expensive, deadly and burdensome diseases in this century. It has the fastest-growing disease burden in China. Apolipoprotein E (APOE) polymorphic alleles are generally considered to be the primary genetic determinant of AD risk: individuals with the E4 allele are at increased risk of AD compared with individuals with the more common E3 allele. Since the intensity of the association varies among different ethnic groups, a separate meta-analysis of the Chinese population is needed. We searched Chinese and English databases to sift through literature over the past 20 years. Data on the APOE genotype and AD were collected for correlation analysis. OR was calculated according to APOE allele and genotype. A publication bias analysis and sensitivity analysis were performed, and the main results were further verified by subgroup analysis. The 116 eligible studies enrolled 23,396 patients with AD and 25,568 healthy controls. The study subjects covered at least 30 of the 34 provincial-level administrative regions (including Taiwan). The partial sex ratio was as follows: AD male/female; 10,291/11,240; control male/female, 11,304/12,428, $${\upchi }^{2}$$ χ 2 = 0.122, P = 0.727. The results of the meta-analysis of alleles showed that I2 > 50% and Q statistics were significant for all genotypes; therefore, the random effect model was selected. The frequency of the ApoE ε4 allele in AD was higher than that in healthy controls, and the difference was statistically significant (OR 2.847, 95% CI [2.611–3.101], P P P P P P P P P

Apolipoprotein E (APOE) plays a pivotal role in lipid including cholesterol metabolism. The APOE ε4 (APOE4) allele is a major genetic risk factor for Alzheimer’s and cardiovascular diseases. Although APOE has recently been associated with increased susceptibility to infections of several viruses, whether and how APOE and its isoforms affect SARS-CoV-2 infection remains unclear. Here, we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients. Utilizing multiple protein interaction assays, we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2; and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2, a key docking site for SARS-CoV-2 Spike protein. In addition, immuno-imaging assays using confocal, super-resolution, and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spike-mediated viral entry into cells. Interestingly, while having a comparable binding affinity to ACE2, APOE4 inhibits viral entry to a lesser extent compared to APOE3, which is likely due to APOE4’s more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2. Furthermore, APOE ε4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed. Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2, which may explain in part increased COVID-19 infection and disease severity in APOE ε4 carriers.

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing sporadic Alzheimer's disease. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral APOE3 allele remains unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a lipid-accumulated state that renders microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia in response to neuronal conditioned media, we established that neuronal cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro-inflammatory signals. Through decreased uptake of extracellular fatty acids and lipoproteins, we identified that APOE4 microglia disrupts the coordinated activity of neuronal ensembles. These findings suggest that abnormal neuronal network-level disturbances observed in Alzheimer's disease patients harboring APOE4 may in part be triggered by impairment in lipid homeostasis in non-neuronal cells.