Summary Alzheimer's disease is the most common cause of dementia in elderly people. Research into Alzheimer's disease therapy has been at least partly successful in terms of developing symptomatic ...treatments, but has also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer's disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer's disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer's disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomised controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer's disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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The worldwide economic impact of dementia 2010 Wimo, Anders; Jönsson, Linus; Bond, John ...
Alzheimer's & dementia,
2013, January 2013, 2013-Jan, 2013-01-00, 20130101, Volume:
9, Issue:
1
Journal Article
Peer reviewed
Abstract Objective To acquire an understanding of the societal costs of dementia and how they affect families, health and social care services, and governments to improve the lives of people with ...dementia and their caregivers. Methods The basic design of this study was a societal, prevalence-based, gross cost-of-illness study in which costs were aggregated to World Health Organization regions and World Bank income groupings. Results The total estimated worldwide costs of dementia were US$604 billion in 2010. About 70% of the costs occurred in western Europe and North America. In such high-income regions, costs of informal care and the direct costs of social care contribute similar proportions of total costs, whereas the direct medical costs were much lower. In low- and middle-income countries, informal care accounts for the majority of total costs; direct social care costs are negligible. Conclusions Worldwide costs of dementia are enormous and distributed inequitably. There is considerable potential for cost increases in coming years as the diagnosis and treatment gap is reduced. There is also likely to be a trend in low- and middle-income countries for social care costs to shift from the informal to the formal sector, with important implications for future aggregated costs and the financing of long-term care. Only by investing now in research and the development of cost-effective approaches to early diagnosis and care can future societal costs be anticipated and managed.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBJE, SBMB, UL, UM, UPUK
Glycosylation is one of the most common, and the most complex, forms of post‐translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer ...disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid β‐peptide (Aβ), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid β‐peptide (Aβ), i.e. γ‐secretase and β‐secretase, also have roles in protein glycosylation. For instance, γ‐secretase and β‐secretase affect the extent of complex N‐glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of γ‐secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v‐ATPase, and tyrosine‐related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients.
This review summarizes the current knowledge on the roles of protein glycosylation in Alzheimer Disease (AD). Defects in glycosylation of two proteins of major importance in AD, Tau and the amyloid precursor protein (APP), as well as other proteins, have been reported in AD. These findings indicate that protein glycosylation is of importance in AD pathogenesis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background The purpose of this study was to update the previous estimate of the worldwide cost of dementia in 2005 to 2009. Methods The cost model is based on prevalence estimates, country ...and region-specific data on Gross Domestic Product per person and average wage, with results from previously published cost-of-illness studies in different countries. Prevalence figures are updated to 2009 and costs were adjusted to 2009 constant US dollars ($). Results The total worldwide societal cost of dementia, based on a dementia population of 34.4 million demented persons, was estimated to $422 billion in 2009, including $142 billion for informal care (34%). Conclusions The worldwide cost of dementia has increased by 34% (18% in fixed prices) between 2005 and 2009.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBJE, SBMB, UL, UM, UPUK
Alzheimer’s disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently ...there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.
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•Tau tageting therapeutics are in the main focus for development of drugs for Alzheimers disease.•Small molecules targeting tau aggregation, post-translational modification modulation, degradation are covered.•A glimpse of small molecules targeting tauopathy currently under clinical trials is given.•A quick look into multi-targeting small molecules is provided.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
...a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suffering and the enormous societal cost of AD. In ...2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries.2 In 2012 and 2015, the World Health Organization (WHO) presented reports in which it acknowledged this trend--sometimes described in terms of a fast-growing epidemic--and concluded that AD and other dementias should be regarded as a global public health priority.3,4 Similar policy declarations have been made by the European Union5 (EU) and by some individual countries. Care for people with dementia is provided by several sectors in society, with the social-care (long-term care and home services) and informal-care (provided by non-professional caregivers) sectors accounting for the greatest proportion of costs--even greater than the cost of direct medical care.6 In cost-of-illness studies, total societal cost estimates for dementia in Europe in 2010 were between $238·6 billion6 and euro105·6 billion.7 The economic costs of caring for a growing number of people with AD and other dementias are formidable, but the combined economic and societal burden of dementia is more daunting still, corresponding to the aggregate burden of people with dementia and their next of kin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We explored the role of age, gender, and socioeconomic status in the occurrence of chronic diseases and multimorbidity in 1099 elderly participants in the Kungsholmen Project. Cardiovascular and ...mental diseases were the most common chronic disorders. Of the participants, 55% had multimorbidity. Advanced age, female gender, and lower education were independently associated with a more than 50% increased risk for multimorbidity. Multimorbidity is the most common clinical picture of the elderly and may be increased by unhealthy behaviors linked to education.
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CEKLJ, DOBA, FSPLJ, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ...ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer’s disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER–mitochondria interplay in the brain has so far remained unknown. Here, we studied ER–mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and σ1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP) Swₑ/Lₒₙ mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER–mitochondria bridging complex, inositol-1,4,5-triphosphate receptor–voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid β-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER–mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER–mitochondria contacts and cross-talk in AD pathology.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The recent availability of longitudinal data on the possible association of different lifestyles with dementia and Alzheimer's disease (AD) allow some preliminary conclusions on this topic. This ...review systematically analyses the published longitudinal studies exploring the effect of social network, physical leisure, and non-physical activity on cognition and dementia and then summarises the current evidence taking into account the limitations of the studies and the biological plausibility. For all three lifestyle components (social, mental, and physical), a beneficial effect on cognition and a protective effect against dementia are suggested. The three components seem to have common pathways, rather than specific mechanisms, which might converge within three major aetiological hypotheses for dementia and AD: the cognitive reserve hypothesis, the vascular hypothesis, and the stress hypothesis. Taking into account the accumulated evidence and the biological plausibility of these hypotheses, we conclude that an active and socially integrated lifestyle in late life protects against dementia and AD. Further research is necessary to better define the mechanisms of these associations and better delineate preventive and therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau ...proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. Methods We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50–85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov , number NCT01850238 ; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov , number NCT02031198. Findings This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 53% vaccinated patients 92 individual events). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. Interpretation AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. Funding AXON Neuroscience SE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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