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Physiological Reviews Jul 2021The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and... (Review)
Review
The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and genetic subtypes and to formulate the first pathogenic hypothesis. Thanks to biomarkers and new technologies, the concept of AD then rapidly changed from a static view of an amnestic dementia of the presenium to a biological entity that could be clinically manifested as normal cognition or dementia of different types. What is clearly emerging from studies is that AD is heterogeneous in each aspect, such as amyloid composition, tau distribution, relation between amyloid and tau, clinical symptoms, and genetic background, and thus it is probably impossible to explain AD with a single pathological process. The scientific approach to AD suffers from chronological mismatches between clinical, pathological, and technological data, causing difficulty in conceiving diagnostic gold standards and in creating models for drug discovery and screening. A recent mathematical computer-based approach offers the opportunity to study AD in real life and to provide a new point of view and the final missing pieces of the AD puzzle.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Brain; Humans; Peptide Fragments; Plaque, Amyloid
PubMed: 33475022
DOI: 10.1152/physrev.00015.2020 -
International Journal of Molecular... Mar 2023Alzheimer's disease is one of the most commonly diagnosed cases of senile dementia in the world. It is an incurable process, most often leading to death. This disease is... (Review)
Review
Alzheimer's disease is one of the most commonly diagnosed cases of senile dementia in the world. It is an incurable process, most often leading to death. This disease is multifactorial, and one factor of this is inflammation. Numerous mediators secreted by inflammatory cells can cause neuronal degeneration. Neuritis may coexist with other mechanisms of Alzheimer's disease, contributing to disease progression, and may also directly underlie AD. Although much has been established about the inflammatory processes in the pathogenesis of AD, many aspects remain unexplained. The work is devoted in particular to the pathomechanism of inflammation and its role in diagnosis and treatment. An in-depth and detailed understanding of the pathomechanism of neuroinflammation in Alzheimer's disease may help in the development of diagnostic methods for early diagnosis and may contribute to the development of new therapeutic strategies for the disease.
Topics: Humans; Alzheimer Disease; Inflammation; Neuritis
PubMed: 37047492
DOI: 10.3390/ijms24076518 -
The Journal of Biological Chemistry 2021Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials.... (Review)
Review
Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology are yet to be proved effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the AD brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here, we review these essential elements of AD for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.
Topics: Alzheimer Disease; Animals; Brain; Copper; Ferroptosis; Humans; Iron; Phospholipid Hydroperoxide Glutathione Peroxidase; Plaque, Amyloid; Selenium; Zinc
PubMed: 33219130
DOI: 10.1074/jbc.REV120.008207 -
Nature Reviews. Neurology Sep 2019Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an... (Review)
Review
Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Brain; Genetic Predisposition to Disease; Humans; Plaque, Amyloid; Polymorphism, Genetic
PubMed: 31367008
DOI: 10.1038/s41582-019-0228-7 -
Tidsskrift For Den Norske Laegeforening... May 2021Alzheimer's disease is the most common cause of dementia globally. Its prevalence will increase considerably in the years to come, in pace with the increasing proportion...
Alzheimer's disease is the most common cause of dementia globally. Its prevalence will increase considerably in the years to come, in pace with the increasing proportion of older people. No disease-modifying treatment is currently available. Measures to mitigate risk in mid-life may potentially prevent or postpone up to 40 % of dementia cases at group level.
Topics: Aged; Alzheimer Disease; Humans
PubMed: 33950641
DOI: 10.4045/tidsskr.20.0919 -
Journal of Sleep Research Aug 2021Suboptimal sleep causes cognitive decline and probably accelerates Alzheimer's Disease (AD) progression. Several sleep interventions have been tested in established AD... (Review)
Review
Suboptimal sleep causes cognitive decline and probably accelerates Alzheimer's Disease (AD) progression. Several sleep interventions have been tested in established AD dementia cases. However early intervention is needed in the course of AD at Mild Cognitive Impairment (MCI) or mild dementia stages to help prevent decline and maintain good quality of life. This systematic review aims to summarize evidence on sleep interventions in MCI and mild AD dementia. Seven databases were systematically searched for interventional studies where ≥ 75% of participants met diagnostic criteria for MCI/mild AD dementia, with a control group and validated sleep outcome measures. Studies with a majority of participants diagnosed with Moderate to Severe AD were excluded. After removal of duplicates, 22,133 references were returned in two separate searches (August 2019 and September 2020). 325 full papers were reviewed with 18 retained. Included papers reported 16 separate studies, total sample (n = 1,056), mean age 73.5 years. 13 interventions were represented: Cognitive Behavioural Therapy - Insomnia (CBT-I), A Multi-Component Group Based Therapy, A Structured Limbs Exercise Programme, Aromatherapy, Phase Locked Loop Acoustic Stimulation, Transcranial Stimulation, Suvorexant, Melatonin, Donepezil, Galantamine, Rivastigmine, Tetrahydroaminoacridine and Continuous Positive Airway Pressure (CPAP). Psychotherapeutic approaches utilising adapted CBT-I and a Structured Limbs Exercise Programme each achieved statistically significant improvements in the Pittsburgh Sleep Quality Index with one study reporting co-existent improved actigraphy variables. Suvorexant significantly increased Total Sleep Time and Sleep Efficiency whilst reducing Wake After Sleep Onset time. Transcranial Stimulation enhanced cortical slow oscillations and spindle power during daytime naps. Melatonin significantly reduced sleep latency in two small studies and sleep to wakefulness transitions in a small sample. CPAP demonstrated efficacy in participants with Obstructive Sleep Apnoea. Evidence to support other interventions was limited. Whilst new evidence is emerging, there remains a paucity of evidence for sleep interventions in MCI and mild AD highlighting a pressing need for high quality experimental studies exploring alternative sleep interventions.
Topics: Alzheimer Disease; Cognitive Dysfunction; Humans; Quality of Life; Sleep
PubMed: 33289311
DOI: 10.1111/jsr.13229 -
Biochemical Pharmacology May 2023Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions of people worldwide, with both prevalence and incidence increasing... (Review)
Review
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases that affect millions of people worldwide, with both prevalence and incidence increasing with age. It is characterized by cognitive decline associated, specifically, with degeneration of cholinergic neurons. The problem of this disease is even more fundamental as the available therapies remain fairly limited and mainly focused on symptoms' relief. Although the aetiology of the disease remains elusive, two main pathological hallmarks are described: i) presence of neurofibrillary tangles formed by unfolded protein aggregates (hyperphosphorylated Tau protein) and ii) presence of extracellular aggregates of amyloid-beta peptide. Given the complexity surrounding the pathogenesis of the disease, several potential targets have been highlighted and interrelated upon its progression, such as oxidative stress and the accumulation of metal ions. Thus, advances have been made on the development of innovative multitarget therapeutical compounds to delay the disease progression and restore cell function. This review focuses the ongoing research on new insights and emerging disease-modifying drugs for AD treatment. Furthermore, classical and novel potential biomarkers for early diagnosis of the disease, and their role in assisting on the improvement of targeted therapies will also be approached.
Topics: Humans; Alzheimer Disease; tau Proteins; Amyloid beta-Peptides; Oxidative Stress
PubMed: 36996971
DOI: 10.1016/j.bcp.2023.115522 -
Neurologic Clinics May 2023Reviewing the research presented in this article, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex... (Review)
Review
Reviewing the research presented in this article, it is evident that from an epidemiological perspective, it is important to evaluate the extent to which findings of sex and gender differences in Alzheimer's dementia (AD) are due to differences in longevity, survival bias, and comorbidities. Medical, genetic, psychosocial, and behavioral factors, in addition to hormonal factors, can differentially affect the risk and progression of AD in women versus men. Further, evaluation of sex differences in AD progression and the trajectory of change in cognitive function, neuroimaging, cerebrospinal fluid (CSF), and blood-based biomarkers of AD is needed. Finally, identifying sex differences in AD biomarkers and change across the lifespan is critical for the planning of prevention trials to reduce the risk of developing AD.
Topics: Female; Humans; Male; Alzheimer Disease; Sex Factors; Sex Characteristics; Disease Progression; Biomarkers; tau Proteins
PubMed: 37030962
DOI: 10.1016/j.ncl.2023.01.001 -
Molecular Biology Reports Jul 2021Alzheimer's disease (AD) is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature. The currently approved therapy... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and their combination therapy provides only temporary symptomatic relief. Sincere efforts have been made by the researchers globally to identify new targets, discover, and develop novel therapeutic agents for the treatment of AD. This brief review article is intended to cover the recent advances in drug development and emerging therapeutic agents for AD acting at different targets. The article is compiled using various scientific online databases and by referring to clinicaltrials.gov and ALZFORUM (alzforum.org) websites. The upcoming therapies act on one or more targets including amyloids (secretases, Aβ production, amyloid deposition, and immunotherapy), tau proteins (tau phosphorylation/aggregation and immunotherapy) and neuroinflammation in addition to other miscellaneous targets. Despite the tremendous improvement in our understanding of the underlying pathophysiology of AD, only aducanumab was approved by FDA for the treatment of AD in 18 years i.e., since 2003. Hence, it is concluded that novel therapeutic strategies are required to discover and develop therapeutic agents to fight against the century old AD.
Topics: Alzheimer Disease; Animals; Biomarkers; Clinical Trials as Topic; Disease Management; Disease Susceptibility; Drug Development; Humans; Molecular Targeted Therapy; Treatment Outcome
PubMed: 34181171
DOI: 10.1007/s11033-021-06512-9 -
International Journal of Molecular... Sep 2021Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses... (Review)
Review
Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood-brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Brain; Humans; Insulin; Insulin Resistance; Neurogenesis; Oxidative Stress
PubMed: 34576151
DOI: 10.3390/ijms22189987