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Acta Neuropathologica Feb 2015Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift... (Review)
Review
Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Neurons
PubMed: 25604547
DOI: 10.1007/s00401-015-1386-3 -
Journal of Alzheimer's Disease : JAD 2018
Topics: Alzheimer Disease; Clinical Trials as Topic; Humans
PubMed: 29782320
DOI: 10.3233/JAD-179945 -
Current Biology : CB Jun 2018The German psychiatrist and neuropathologist Alois Alzheimer was fascinated by the symptoms of Auguste D., a 50-year-old woman admitted to the Frankfurt Psychiatric...
The German psychiatrist and neuropathologist Alois Alzheimer was fascinated by the symptoms of Auguste D., a 50-year-old woman admitted to the Frankfurt Psychiatric Hospital in 1901 who suffered from memory disturbances, paranoia and progressive confusion. After her death and autopsy, Alzheimer described histological alterations in her brain that later came to be known as amyloid plaques and neurofibrillary tangles (Figure 1). The case report was published in a psychiatric textbook some years later, and this peculiar and (at the time) seemingly rare illness was later named Alzheimer's disease.
Topics: Alzheimer Disease; Brain; Humans; Plaque, Amyloid; Risk Factors
PubMed: 29870699
DOI: 10.1016/j.cub.2018.04.080 -
Sante Publique (Vandoeuvre-les-Nancy,... 2020Many countries have answered the call from the World Health Organization, and developed or implemented Alzheimer Plans. Some plans anchored the majority of the care for...
Many countries have answered the call from the World Health Organization, and developed or implemented Alzheimer Plans. Some plans anchored the majority of the care for persons living with dementia in specialized care settings, while others anchored it in primary care. In this article we present the Quebec Alzheimer Plan, which is being implemented in Family Medicine Groups, primary care interdisciplinary clinics, across the Canadian province. The Quebec Alzheimer Plan aims to enable primary healthcare teams of physicians, nurses and/or social workers to provide access to personalized, coordinated assessment and treatment services for people living with dementia and their caregivers. The Quebec Alzheimer Plan enables and empowers primary care clinicians to detect, diagnose, treat and follow-up the vast majority of patients/caregivers. A major strength of the Quebec Alzheimer Plan strategy is the embedded evaluation to inform implementation and its flexibility to allow local adaptations. We are discussing that it is feasible and advantageous to anchor dementia care in an interprofessional primary care setting.
Topics: Alzheimer Disease; Canada; Family Practice; Humans; Primary Health Care; Quebec
PubMed: 33512104
DOI: 10.3917/spub.204.0375 -
Continuum (Minneapolis, Minn.) Apr 2016This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD). (Review)
Review
PURPOSE OF REVIEW
This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD).
RECENT FINDINGS
In recent years, significant advances have been made in the fields of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our ability to visualize amyloid pathology in the living human brain. The newly revised criteria for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the underlying pathology. Guidelines for the responsible use of amyloid positron emission tomography (PET) have been developed, and the clinical and economic implications of amyloid PET imaging are actively being explored.
SUMMARY
Our improved understanding of the clinical onset, progression, neuroimaging, pathologic features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and future therapeutic interventions.
Topics: Alzheimer Disease; Cognition Disorders; Disease Progression; Humans; Neuropsychological Tests; Psychiatric Status Rating Scales
PubMed: 27042902
DOI: 10.1212/CON.0000000000000307 -
Nature Apr 2023
Topics: Humans; Alzheimer Disease; Forecasting
PubMed: 37016121
DOI: 10.1038/d41586-023-00954-w -
Nature Reviews. Disease Primers May 2021
Topics: Alzheimer Disease; Humans
PubMed: 33986300
DOI: 10.1038/s41572-021-00275-0 -
Dementia and Geriatric Cognitive... 2020Alzheimer disease (AD), the most common form of dementia, is a heterogenous disorder with various pathobiological subtypes. In addition to the 4 major subtypes based on... (Review)
Review
Alzheimer disease (AD), the most common form of dementia, is a heterogenous disorder with various pathobiological subtypes. In addition to the 4 major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy [MA]), several other clinical variants showing distinct regional patterns of tau burden have been identified: nonamnestic, corticobasal syndromal, primary progressive aphasia, posterior cortical atrophy, behavioral/dysexecutive, and mild dementia variants. Among the subtypes, differences were found in age at onset, sex distribution, cognitive status, disease duration, APOE genotype, and biomarker levels. The patterns of key network destructions parallel the tau and atrophy patterns of the AD subgroups essentially. Interruption of key networks, in particular the default-mode network that is responsible for cognitive decline, is consistent in hetero-genous AD groups. AD pathology is often associated with co-pathologies: cerebrovascular lesions, Lewy pathology, and TDP-43 proteinopathies. These mixed pathologies essentially influence the clinical picture of AD and may accel-erate disease progression. Unraveling the heterogeneity among the AD spectrum entities is important for opening a window to pathogenic mechanisms affecting the brain and enabling precision medicine approaches as a basis for developing preventive and ultimately successful disease-modifying therapies for AD.
Topics: Age of Onset; Alzheimer Disease; Atrophy; Brain; Classification; Cognition; Humans; Phylogeny; Precision Medicine; tau Proteins
PubMed: 33429401
DOI: 10.1159/000508625 -
Ugeskrift For Laeger Mar 2017Alzheimer's disease is a neurodegenerative disorder with insidious onset and slow progression. Prevalence is increasing, although not as fast as previously believed. The... (Review)
Review
Alzheimer's disease is a neurodegenerative disorder with insidious onset and slow progression. Prevalence is increasing, although not as fast as previously believed. The clinical diagnosis may be difficult, but diagnostic methods have been introduced and proven to be accurate in supporting the clinical diagnosis. Application of these methods increases, partly due to improved awareness of cognitive symptoms and the relevance of early detection and diagnosis, in particular when more efficient disease-modifying drugs become available. Currently, only symptomatic treatment can be prescribed, and focus should be on potential prophylactic strategies.
Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Excitatory Amino Acid Antagonists; Humans; Memantine; Risk Factors
PubMed: 28330540
DOI: No ID Found -
Clinica Chimica Acta; International... Oct 2015Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is histologically characterized by accumulation of amyloid-β... (Review)
Review
Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is histologically characterized by accumulation of amyloid-β protein (Aβ) on extracellular plaques and deposition of hyperphosphorylated tau protein in intracellular neurofibrillary tangles. Several studies have shown that obesity may precede dementia and that lifestyle factors play a critical role in the onset of AD. Furthermore, accumulating evidence indicates that obesity is an independent risk factor for developing AD. In this scenario, the understanding of the role of adipose tissue in brain health is essential to clarify the establishment of demential processes. The objective of this work was to review studies regarding leptin, an anorexigenic peptide hormone synthesized in adipocytes, in the context of dementia. Some authors proposed that leptin evaluation might be a better predictor of dementia than traditional anthropometric measures. Leptin, once established as a biomarker, could enhance the understanding of late-onset AD risk over the life course, as well as the clinical progression of prodromal state to manifested AD. Other studies have proposed that leptin presents neuroprotective activities, which could be explained by inhibiting the amyloidogenic process, reducing the levels of tau protein phosphorylation and improving the cognitive function.
Topics: Alzheimer Disease; Animals; Humans; Leptin; Phosphorylation; Polymorphism, Genetic; Receptors, Leptin
PubMed: 26279362
DOI: 10.1016/j.cca.2015.08.009