The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since ...then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late‐stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late‐stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta‐analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild‐to‐moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or ‘mild cognitive impairment due to Alzheimer's disease’, for drugs considered to be disease modifying. The duration of trials has remained at 6–12 months for drugs intended to improve symptoms; 18‐ to 24‐month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early‐stage Alzheimer's disease trial samples using biomarkers and phase‐specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late‐phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.
Pathways to Alzheimer's disease Hardy, J.; Bogdanovic, N.; Winblad, B. ...
Journal of internal medicine,
March 2014, Letnik:
275, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Recent trials of anti‐amyloid agents have not produced convincing improvements in clinical outcome in Alzheimer's disease; however, the reason for these poor or inconclusive results remains unclear. ...Recent genetic data continue to support the amyloid hypothesis of Alzheimer's disease with protective variants being found in the amyloid gene and both common low‐risk and rare high‐risk variants for disease being discovered in genes that are part of the amyloid response pathways. These data support the view that genetic variability in how the brain responds to amyloid deposition is a potential therapeutic target for the disease, and are consistent with the notion that anti‐amyloid therapies should be initiated early in the disease process.
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Objective. We aimed to disentangle the effect of chronic multimorbidity and disability on 3‐year functional decline and survival in the elderly.
Design. Prospective cohort study with a mean of ...follow‐up of 2.8 years.
Setting. Swedish elderly persons from the Kungsholmen Project (1987–2000).
Subjects. A total of 1099 subjects, 77–100 years old, living in the community and institutions.
Main outcome measurements. Medical diagnoses (based on clinical examination, drug use, medical records and blood tests), and functional assessment (according to Katz Index) at baseline were investigated in relation to functional decline and death occurring during follow‐up.
Results. At baseline, 12.1% of participants had disability, and 52.3% were affected by multimorbidity. During follow‐up, 363 persons died and 85 worsened in functioning. The number of chronic conditions incrementally increased the risk of functional decline hazard ratio (HR) increased from 1.5 in subjects with one disease to 6.2 in persons with 4+ diseases. However, this was not the case for mortality, as the HR of death was the same for people with one disease as well as 4+ diseases (HR = 2.3). Baseline disability had the highest impact on survival, independently of number of diseases HR = 8.1; 95% confidence interval (CI) = 4.8–13.7 in subjects with one disease and HR = 7.7; 95% CI = 4.7–12.6 in those with 2+ diseases.
Conclusions. In the elderly subjects, chronic disability rather than multimorbidity emerged as the strongest negative prognostic factor for functionality and survival.
To investigate the relation of diabetes to dementia, Alzheimer disease (AD), and vascular dementia (VaD), through analyses of incidence, mortality, and neuropathologic outcomes in a prospective ...population-based study of the oldest old.
The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ≥85 years on April 1, 1991. Survivors were reexamined in 1994, 1996, 1999, and 2001. Autopsies were performed in 291 persons who died during the follow-up (48% of total population). Diabetes was assessed according to self-report, medical record of physician-diagnosed diabetes, or use of antidiabetic medication. Macroscopic infarcts were identified from 1-cm coronal slices of cerebral hemispheres, 5-mm transverse brainstem slices, and sagittal cerebellum slices. Methenamine silver staining was used for β-amyloid, methenamine silver-Bodian staining for neurofibrillary tangles, and modified Bielschowsky method for neuritic plaques. Cox proportional hazards and multiple logistic regression models were used to analyze the association of diabetes with dementia and neuropathology, respectively.
Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality. Individuals with diabetes were less likely to have β-amyloid (hazard ratio HR 95% confidence interval (CI) was 0.48 0.23-0.98) and tangles (HR 95% CI 0.72 0.39-1.33) but more likely to have cerebral infarcts (HR 95% CI 1.88 1.06-3.34) after all adjustments.
Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE ε4 carriers) results in increased dementia risk.
Heart failure and Alzheimer′s disease Cermakova, P.; Eriksdotter, M.; Lund, L. H. ...
Journal of internal medicine,
April 2015, Letnik:
277, Številka:
4
Journal Article
Recenzirano
Odprti dostop
It has recently been proposed that heart failure is a risk factor for Alzheimer′s disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the ...dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer′s disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.
The Swedish Dementia Registry (SveDem) was developed with the aim to improve the quality of diagnostic work-up, treatment and care of patients with dementia disorders in Sweden.
SveDem is an internet ...based quality registry where several indicators can be followed over time. It includes information about the diagnostic work-up, medical treatment and community support (www.svedem.se). The patients are diagnosed and followed-up yearly in specialist units, primary care centres or in nursing homes.
The database was initiated in May 2007 and covers almost all of Sweden. There were 28 722 patients registered with a mean age of 79.3 years during 2007-2012. Each participating unit obtains continuous online statistics from its own registrations and they can be compared with regional and national data. A report from SveDem is published yearly to inform medical and care professionals as well as political and administrative decision-makers about the current quality of diagnostics, treatment and care of patients with dementia disorders in Sweden.
SveDem provides knowledge about current dementia care in Sweden and serves as a framework for ensuring the quality of diagnostics, treatment and care across the country. It also reflects changes in quality dementia care over time. Data from SveDem can be used to further develop the national guidelines for dementia and to generate new research hypotheses.
There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic ...cross‐β‐sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease‐modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β‐peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.
Content List – Read more articles from the symposium: Amyloid ‐ a multifaceted player in human health and disease.
Dementia disorders are today considered to be a major driver of costs in health care and social systems and worrying estimates of future dementia prevalence have been presented. It is of great ...interest for policy makers to have an estimate of dementia disorders’ contribution to global social and health care costs, particularly in light of the demographic prognoses. The worldwide costs of dementia were estimated from prevalence figures for different regions, and cost-of-illness studies from key countries using a model based on the relationship between direct costs of care per demented and the gross domestic product per capita in each country. The worldwide direct costs for dementia in 2003 are estimated at 156 billion USD in the main scenario based on a worldwide prevalence of 27.7 million demented persons (sensitivity analysis: 129–159 billion USD). Ninety-two percent of the costs are found in the advanced economies with 38% of the prevalence. Although there are several sources of uncertainty, it is obvious that the worldwide costs are substantial and the expected increase in elderly people in the developing countries presents a great challenge.
To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI).
We ...followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria.
Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk RR = 1.8 1.2 to 2.7 per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 1.0 to 3.6 per symptom).
The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.
Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature ...of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood–brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near‐future strategy.
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