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BACKGROUND: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. METHODS: Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. RESULTS: In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1ß response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. CONCLUSIONS: Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.
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Aterosclerose , Serina-Treonina Quinases TOR , Camundongos , Animais , Alvo Mecanístico do Complexo 2 de Rapamicina , Serina-Treonina Quinases TOR/metabolismo , Macrófagos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fatores de Transcrição/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismoRESUMO
Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.
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Cardiomiopatias , Leucemia Mieloide Aguda , Sulfonamidas , Masculino , Humanos , Feminino , Estudos Retrospectivos , Resultado do Tratamento , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Cardiomiopatias/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Electrophoresis of a weakly charged dielectric droplet with constant surface charge density in a chargeless cylindrical pore is investigated theoretically in this study, focusing on the boundary confinement effect of the double layer, which in turn determines the ultimate motion of the droplet. A patched pseudo-spectral method based on the Chebyshev polynomial is adopted to solve the resulting governing fundamental electrokinetic equations. Mobility reversal, among other interesting phenomena, is observed when the droplet is in a narrow cylindrical pore. No such observation was made in the corresponding motion of a rigid particle. The droplet with a thick double layer may even move against the prediction based on the Coulomb electrostatic law, for instance, a positively charged droplet may move against the electric field. The significant enhancement of the motion-deterring double layer polarization due to the severe steric boundary confinement within a narrow cylindrical pore is found to be responsible for this seemingly peculiar phenomenon. Moreover, smaller droplets may move in the opposite direction of the larger ones. The results are useful in capillary electrophoresis involving droplets in particular and migration of droplets through narrow channels in general.
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The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Genótipo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Apolipoproteína E4/genéticaRESUMO
INTRODUCTION: Healthy aging relies on mitochondrial functioning because this organelle provides energy and diminishes oxidative stress. Single nucleotide polymorphisms (SNPs) in TOMM40, a critical gene that produces the outer membrane protein TOM40 of mitochondria, have been associated with mitochondrial dysfunction and neurodegenerative processes. Yet it is not clear whether or how the mitochondria may impact human longevity. We conducted this review to ascertain which SNPs have been associated with markers of healthy aging. METHODS: Using the PRISMA methodology, we conducted a systematic review on PubMed and Embase databases to identify associations between TOMM40 SNPs and measures of longevity and healthy aging. RESULTS: Twenty-four articles were selected. The TOMM40 SNPs rs2075650 and rs10524523 were the two most commonly identified and studied SNPs associated with longevity. The outcomes associated with the TOMM40 SNPs were changes in BMI, brain integrity, cognitive functions, altered inflammatory network, vulnerability to vascular risk factors, and longevity. DISCUSSIONS: Our systematic review identified multiple TOMM40 SNPs potentially associated with healthy aging. Additional research can help to understand mechanisms in aging, including resilience, prevention of disease, and adaptation to the environment.
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Envelhecimento Saudável , Longevidade , Envelhecimento/genética , Envelhecimento Saudável/genética , Humanos , Longevidade/genética , Proteínas de Membrana Transportadoras/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Traditional clinical interventions yield few positive effects on diet. The Healthy Teaching Kitchen (HTK) program implemented by the Veterans Health Administration at sites across the United States delivers interactive nutrition and culinary education, guided instruction, and social opportunities for patients and caregivers. We report HTK outcomes of veterans' self-reported acceptability, self-efficacy for dietary change, and dietary and cooking habits. The HTK program is acceptable and feasible and may empower participants to improve health.
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Culinária/métodos , Dieta Saudável/métodos , Promoção da Saúde/organização & administração , Ciências da Nutrição/educação , Saúde dos Veteranos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
INTRODUCTION: Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person's risk of developing both Alzheimer's disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD. METHODS: Genomic DNA from postmortem brain tissues (frontal lobe and cerebellum) of neuropathological pure (np) controls and npAD, LBD + AD, and npLBD subjects were bisulfite pyrosequenced. DNA methylation levels of two APOE subregions were then compared for these groups. RESULTS: APOE DNA methylation was significantly reduced in npLBD compared with np controls, and methylation levels were lowest in the LBD + AD group. DISCUSSION: Given that npLBD and npAD postmortem brains shared a similar reduction in APOE methylation, it is possible that an aberrant epigenetic change in APOE is linked to risk for both diseases.
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Apolipoproteínas E/genética , Encéfalo , Metilação de DNA/genética , Lobo Frontal/patologia , Doença por Corpos de Lewy/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Autopsia , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Genótipo , Humanos , Doença por Corpos de Lewy/patologia , MasculinoRESUMO
Ribonucleic acid therapeutics have advantages over biologics and small molecules, including lower safety risks, cheaper costs, and extensive targeting flexibility, which is rapidly fueling the expansion of the field. This is made possible by breakthroughs in the field of drug delivery, wherein lipid nanoparticles (LNPs) are one of the most clinically advanced systems. LNP formulations that are currently approved for clinical use typically contain an ionizable cationic lipid, a phospholipid, cholesterol, and a polyethylene glycol-lipid; each contributes to the stability and/or effectiveness of LNPs. In this review, we discuss the immunomodulatory effects associated with each of the lipid components. We highlight several studies in which the components of LNPs have been implicated in cellular sensing and explore the pathways involved.
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Nanopartículas , RNA , Lipídeos , Lipossomos , Imunidade , RNA Interferente Pequeno/metabolismoRESUMO
Vaccination is one of the most successful measures in modern medicine to combat diseases, especially infectious diseases, and saves millions of lives every year. Vaccine design and development remains critical and involves many aspects, including the choice of platform, antigen, adjuvant, and route of administration. Topical vaccination, defined herein as the introduction of a vaccine to any of the three layers of the human skin, has attracted interest in recent years as an alternative vaccination approach to the conventional intramuscular administration because of its potential to be needle-free and induce a superior immune response against pathogens. In this review, we describe recent progress in developing topical vaccines, highlight progress in the development of delivery technologies for topical vaccines, discuss potential factors that might impact the topical vaccine efficacy, and provide an overview of the current clinical landscape of topical vaccines.
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Vacinação , Vacinas , Humanos , Pele , Adjuvantes Imunológicos , AntígenosRESUMO
The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.
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Doença de Alzheimer , Humanos , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genótipo , Longevidade/genéticaRESUMO
BACKGROUND: Past studies identified a link between weight loss and dementia, but lacked consistent conclusions. We sought to establish this link by examining the weight change profiles before and after dementia diagnosis. METHODS: Using data from the Health and Retirement Study (1996-2020), we examined 13,123 participants. We conducted a nested case-control analysis to assess differences in biennial weight change profile while controlling for BMI, longevity polygenic risk scores, and APOE gene variants. RESULTS: Participants with a memory disorder lost weight (-0.63%) biennially, whereas those without a diagnosis did not (+0.013%, p-value < 0.0001). Our case-control study shows a significant difference (p-value < 0.01) in pre-dementia % weight changes between the cases (-0.29%) and controls (0.19%), but not in post-dementia weight changes. The weight loss group have the highest risk (OR = 2.01; p-value < 0.0001) of developing a memory disorder compared to the stable weight and weight gain groups. The observations hold true after adjusting for BMI, longevity polygenic risk scores, and APOE variant in a multivariable model. CONCLUSIONS: We observe that weight loss in dementia is a physiological process independent of genetic factors associated with BMI and longevity. Pre-dementia weight loss may be an important prognostic criterion to assess a person's risk of developing a memory disorder.
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Demência , Transtornos da Memória , Humanos , Estudos de Casos e Controles , Transtornos da Memória/genética , Redução de Peso/genética , Demência/genética , Apolipoproteínas E/genéticaRESUMO
PURPOSE: The COVID-19 pandemic limited access to community fall prevention programs, thus establishing the need for virtual interventions. Herein, we describe the feasibility, effectiveness, and acceptability of a virtual, multicomponent fall prevention program (MOVing FREEly). METHODS: A team of clinical falls prevention experts developed a six-week multicomponent fall prevention exercise and education class for older community-dwelling adults at risk of falling. Feasibility was measured through class attendance; effectiveness was measured through changes in performance measures, self-report of falling risk, and concern about falling; acceptability was assessed through questionnaires completed immediately upon program completion and at a three-month follow up. RESULTS: A total of 32 patients participated in the MOVing FREEly program. Attendance for education and exercise classes on average was greater than 80% with little attrition. Patient reported reduced concern of falling, improvement in the falls efficacy scale-international (FES-I) short form, and had statistically significant improvement in 30 s sit-to-stand and single-leg balance tests. The program was well received by participants, saving them significant time and costs of travel. CONCLUSIONS: A virtual, multicomponent fall prevention program is feasible and acceptable and effective as reducing falling risk. Future studies can explore the ability of this program to reduce falling incident and injury.
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RATIONALE: The association between self-report falling risk in persons with COPD and hospitalization has not been previously explored. OBJECTIVE: To examine whether self-reported risk is associated with hospitalizations in patients with COPD. METHODS: A secondary analysis from a prospective observational cohort study of veterans with COPD. Participants completed questions from the Stopping Elderly Accidents, Deaths and Injuries (STEADI) tool kit at either baseline or at the end of the 12-month study. A prospective or cross-sectional analysis examined the association between responses to the STEADI questions and risk of all-cause or COPD hospitalizations. RESULTS: Participants (N = 388) had a mean age of 69.6 ± 7.5 years, predominately male (96 %), and 144 (37.1 %) reported having fallen in the last year. More than half reported feeling unsteady with walking (52.6 %) or needing to use their arms to stand up from a chair (61.1 %). A third were concerned about falling (33.3 %). Three questions were associated with all-cause (not COPD) hospitalization in both unadjusted and adjusted cross-sectional analysis (N = 213): "fallen in the past year" (IRR 1.77, 95 % CI 1.10 to 2.86); "unsteady when walking" (IRR 1.88, 95 % CI 1.14 to 3.10); "advised to use a cane or walker" (IRR 1.89, 95 % CI 1.16 to 3.08). CONCLUSIONS: The prevalence of self-reported falling risk was high in this sample of veterans with COPD. The association between falling risk and all-cause hospitalization suggests that non-COPD hospitalizations can negatively impact intrinsic risk factors for falling. Further research is needed to clarify the effects of all-cause hospitalization on falling risk in persons with COPD.
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Doença Pulmonar Obstrutiva Crônica , Humanos , Masculino , Idoso , Pessoa de Meia-Idade , Autorrelato , Estudos Prospectivos , Estudos Transversais , HospitalizaçãoRESUMO
The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.
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Falls are a significant contributor to disability and death among older adults. Despite practice guidelines to increase falls screening in healthcare settings, preventive care for falls continues to be infrequently delivered. Simplifying screening by relying on self-report of balance, gait, or strength concerns, alone may increase the frequency of falls screening. We assessed the diagnostic accuracy of self-report measures of gait, strength, and balance from the Centers for Disease Control and Prevention's Stopping Elderly Accidents, Deaths, and Injuries (STEADI) for identification of fall risk. The criterion standard for fall risk was the Timed Up-and-Go (TUG). Assessments were conducted with 95 adults aged 65 years or older in an outpatient osteoporosis clinic between May 2015 and September 2016. Receiver operating characteristic curve analysis found that two self-report questions ("I feel unsteady with walking" and "I need my arms to stand from a chair") had high discriminatory ability (AUC 0.906; 95% CI 0.870-0.942) to identify those at high fall risk; additional questions did not substantially improve discrimination. These findings suggest that two self-report questions identify those at risk of falling who would benefit from interventions (e.g., physical therapy). Performance testing as part of routine falls screening of older persons in the outpatient setting may be unnecessary.
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Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer's disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40's role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction.
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Doença de Alzheimer/genética , Encéfalo/metabolismo , Proteínas de Membrana Transportadoras/genética , Mitocôndrias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Linhagem Celular , Células Cultivadas , Feminino , Dosagem de Genes , Humanos , Masculino , Potencial da Membrana Mitocondrial , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
PURPOSE: The long-term effects of acetylcholinesterase inhibitors (AChEIs) used in the treatment of patients with various types of dementia remain unclear, largely due to challenges in the study of their discontinuation. We present several unexpected results from a discontinuation trial that might merit further investigation. METHODS: This double-blind, placebo-controlled study of the discontinuation of AChEI medications was conducted in 62 US veterans. Participants were randomized to receive continued treatment with their medication (sham-taper group) or to treatment discontinuation via tapering (real-taper group), over a period of 6 weeks. The primary end point was the patient's/family caregiver's decision to discontinue the study medication. FINDINGS: The study was underpowered to detect a significant between-group difference in the primary end point, but examination of the discontinuation process generated several unexpected results: (1) recruitment proved extremely challenging for a variety of reasons, with <5% of potentially eligible participants enrolled; (2) all 3 patients with Parkinson disease-associated dementia showed a worsening of symptoms when they discontinued their AChEI medication, but they showed improvement after they restarted it; (3) changes in symptom-scale scores varied quite broadly across participants, regardless of treatment arm; (4) unusual effects were noted in the sham-taper arm; and (5) the only significant predictor of the decision to discontinue the study medication was a worsening in the caregiver's mood. IMPLICATIONS: These findings argue for the use of caution in discontinuing AChEIs in patients with Parkinson disease-associated dementia, although there may be potential benefits of a "drug holiday." The findings also urge the consideration of distress on the part of the caregiver while making medication treatment decisions in dementia. Future research must address challenges with recruitment and symptom fluctuations.
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Inibidores da Colinesterase , Demência/tratamento farmacológico , Doença de Parkinson , Acetilcolinesterase , Inibidores da Colinesterase/administração & dosagem , Demência/etiologia , Método Duplo-Cego , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológicoRESUMO
Importance: The ε2 and ε4 alleles of the apolipoprotein E (APOE) gene are associated with Alzheimer disease (AD) risk. Although nearby genetic variants have also been shown to be associated with AD, including rs2075650 in the TOMM40 gene and rs4420638 near the APOC1 gene, it is unknown whether these associations are independent of the ε2 and ε4 alleles. Objective: To assess whether variants near APOE are associated with AD independently of the ε2/ε3/ε4 genotype. Design, Setting, and Participants: In this genetic association study of the Alzheimer's Disease Genetics Consortium imputed genotype at data, 14â¯415 variants near APOE (±500 kilobase) for 18â¯795 individuals with European ancestry were tested for association with AD using 4 logistic mixed models adjusting for sex, cohort, population structure, and relatedness. Model 1 had no APOE adjustment, and model 2 adjusted for the count of ε2 and ε4 alleles. Model 3 was restricted to ε3 homozygotes, and model 4 was restricted to ε4 homozygotes. Data were downloaded from May 31, 2018, to June 3, 2018, and analyzed from November 1, 2018, to June 24, 2020. Main Outcomes and Measures: Alzheimer disease affectation status was defined by clinicians using standard National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association criteria. Association was evaluated using Score tests; results with P < .05 divided by the number of independent tests per model were considered statistically significant. Results: Among the 18â¯795 individuals in the study, 9704 were affected by AD and 9066 were control individuals; the median age at onset/evaluation was 76 (interquartile range, 70-82) years; and 11 167 were female (59.4%). Associations with AD were found for rs2075650 (odds ratio [OR], 2.59; 95% CI, 2.45-2.75; P = 3.19 × 10-228) and rs4420638 (OR, 2.77; 95% CI, 2.62-2.94; P = 2.99 × 10-254) without APOE adjustment. Although rs2075650 was nominally associated with AD among the ε4 homozygotes (OR, 1.33; 95% CI, 1.00-1.77; P = .047), the association between rs4420638 and AD was eliminated by APOE adjustment (model 2 OR, 1.06 [95% CI, 0.96-1.18; P = .24]; model 3 OR, 1.13 [95% CI, 0.95-1.34; P = .18]; model 4 OR, 0.90 [95% CI, 0.56-1.45; P = .66]). There was a significant association between rs192879175 and AD among ε3 homozygotes (OR, 0.50; 95% CI, 0.37-0.68; P = 8.30 × 10-6). Conclusions and Relevance: The results of this genetic association study suggest that ε2/ε3/ε4 alleles are not the only variants in the APOE region that are associated with AD risk. Additional work with independent data is needed to replicate these results.
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Alelos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Variação Genética , Genótipo , População Branca/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Modelos Logísticos , Masculino , Fatores de RiscoRESUMO
INTRODUCTION: Age of onset modifiers are of considerable importance in Alzheimer's and related dementias. Arboleda-Valesquez et al., reporting on a single PSEN1 subject, suggested that homozygosity for the Christchurch variant of APOE could represent such a modifier. METHODS: We studied APOE Christchurch and Kloth-VS genotypes of five dementia age of onset outliers who carried their families' pathogenic variant, but were asymptomatic at ages beyond the families' average age of onset. RESULTS: Four age of onset outliers with PSEN1/2 and MAPT mutations did not carry the Christchurch variant and a fifth individual was also determined to not be homozygous for this variant. Among them, only one subject (APOE ε3/ε3) carries the Klotho-VS heterozygous genotype. DISCUSSION: From a small but informative sample of five age of onset outliers we show that neither the APOE Christchurch nor the Klotho-VS variant is a common age of onset modifier for three genetic forms of dementia. Larger studies of this association and further research is required to identify additional genetic modifiers.
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Doença de Alzheimer , Demência Frontotemporal , Idade de Início , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Demência Frontotemporal/genética , Humanos , Mutação/genética , Presenilina-1/genética , Presenilina-2/genética , Proteínas tau/genéticaRESUMO
The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3'-exon, and this CGI's effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.