BACKGROUND: Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. METHODS: Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level. RESULTS: We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. CONCLUSIONS: Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.

• Keywords
• 3-sulfopropanoic acid, Aggregation, Alzheimer’s disease, Apolipoprotein E, Cerebral organoids, HDX-MS, Lipidomics, Molecular dynamics, Neurodegeneration, Protein crystallography, Proteomics, Tramiprosate,
• MeSH
• Alzheimer Disease * drug therapy   genetics   metabolism   MeSH
• Apolipoprotein E3 genetics   MeSH
• Apolipoprotein E4 * genetics   metabolism   MeSH
• Apolipoproteins E genetics   MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Apolipoprotein E3 MeSH
• Apolipoprotein E4 * MeSH
• Apolipoproteins E MeSH
• tramiprosate MeSH Browser

BACKGROUND: Business process modelling is increasingly used not only by the companies' management but also by scientists dealing with process models. Process modeling is seldom done without decision-making nodes, which is why operational research methods are increasingly included in the process analyses. OBJECTIVE: This systematic literature review aimed to provide a detailed and comprehensive description of the relevant aspects of used operational research techniques in Business Process Model and Notation (BPMN) model. METHODS: The Web Of Science of Clarivate Analytics was searched for 128 studies of that used operation research techniques and business process model and notation, published in English between 1 January 2004 and 18 May 2020. The inclusion criteria were as follows: Use of Operational Research methods in conjunction with the BPMN, and is available in full-text format. Articles were not excluded based on methodological quality. The background information of the included studies, as well as specific information on the used approaches, were extracted. RESULTS: In this research, thirty-six studies were included and considered. A total of 11 specific methods falling into the field of Operations Research have been identified, and their use in connection with the process model was described. CONCLUSION: Operational research methods are a useful complement to BPMN process analysis. It serves not only to analyze the probability of the process, its economic and personnel demands but also for process reengineering.

• Keywords
• BPMN, Business process model and notation, Decision making, OR, Operation Research, Review, Techniques,
• Publication type
• Journal Article MeSH

Increasing life expectancy in modern society is undoubtedly due to improved healthcare, scientific advances in medicine, and the overall healthy lifestyle of the general population. However, this positive trend has led to an increase in the number of older people with a growing need for a sustainable system for the long-term care of this part of the population, which includes social and health services that are essential for a high quality of life. Longevity also brings challenges in the form of a polymorbid geriatric population that places financial pressure on healthcare systems. Regardless, one disease dominates the debate about financial sustainability due to the increasing numbers of people diagnosed, and that is Alzheimer's disease (AD). The presented paper aims to demonstrate the economic burden of social and healthcare services. Data from two regions in the Czech Republic were selected to demonstrate the potential scope of the problem. The future costs connected with AD are calculated by a prediction model, which is based on a population model for predicting the number of people with AD between 2020 and 2070. Based on the presented data from the two regions in the Czech Republic and the prediction model, several trends emerged. There appears to be a significant difference in the annual direct costs per person diagnosed with AD depending on the region in which they reside. This may lead to a significant inequality of the services a person can acquire followed by subsequent social issues that can manifest as a lower quality of life. Furthermore, given the prediction of the growing AD population, the costs expressed in constant prices based on the year 2020 will increase almost threefold during the period 2020-2070. The predicted threefold increase will place additional financial pressure on all stakeholders responsible for social and healthcare services, as the current situation is already challenging.

• Keywords
• Alzheimer’s disease, Czech Republic, costs, prediction model,
• Publication type
• Journal Article MeSH

BACKGROUND: Given the increasing lifespan of the elderly and the higher proportion of older people in the global population, the incidence rate of neurodegenerative diseases is increasing. The aim of this study is to evaluate, by means of computer simulations, developments in the costs of treating and caring for people suffering from Alzheimer's disease (AD) in the EU 28 by 2080, while assuming the introduction of drug administrations at various disease stages. METHODS: Impact analysis leverages a mathematical model that compares five different population development scenarios when introducing different types of drugs to the scenarios but without changing the treatment. Changes in the economic burden are considered as of 2023, when new drugs are expected to enter the market. FINDINGS: The results of the simulations show that by prolonging the length of a person's 'stay' in the Mild, Moderate, or Severe stage, the total cost of care for all persons with AD will increase by 2080. For individual scenarios, the percentage of patients and costs increased as follows: Mild by one year, by 10.61%; Mild by two years, by 17.73%; Moderate by one year, by 16.79%; Moderate by two years, by 34.88%; and Severe by one year, by 23.79%. The change in cost development when prolonging the stay in the Mild cognitive impairment stage (by lowering the incidence by 10%, 30%, or 50%) reduced the cost (by 4.88%, 16.78% and 32.48%, respectively). INTERPRETATION: The results unambiguously show that any intervention prolonging a patient's stay in any stage will incur additional care costs and an increase in the number of persons with AD. Therefore, extending lifespan is important in terms of improving the quality of life of patients, and the introduction of new drugs must consider the additional costs imposed upon society.

• MeSH
• Alzheimer Disease drug therapy   economics   therapy   MeSH
• Longevity MeSH
• Cognitive Dysfunction drug therapy   economics   therapy   MeSH
• Quality of Life MeSH
• Humans MeSH
• Health Care Costs statistics & numerical data   MeSH
• Nootropic Agents economics   therapeutic use   MeSH
• Computer Simulation MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• Nootropic Agents MeSH