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Lancet (London, England) Apr 2021In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will... (Review)
Review
In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.
Topics: Alzheimer Disease; Humans
PubMed: 33667416
DOI: 10.1016/S0140-6736(20)32205-4 -
Molecules (Basel, Switzerland) Dec 2020Alzheimer's disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in... (Review)
Review
Alzheimer's disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to -methyl d-aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Disease Management; Disease Susceptibility; Humans; Neurodegenerative Diseases; Risk Assessment; Risk Factors; Severity of Illness Index; tau Proteins
PubMed: 33302541
DOI: 10.3390/molecules25245789 -
Current Neuropharmacology 2020The only conclusive way to diagnose Alzheimer's is to carry out brain autopsy of the patient's brain tissue and ascertain whether the subject had Alzheimer's or any... (Review)
Review
BACKGROUND
The only conclusive way to diagnose Alzheimer's is to carry out brain autopsy of the patient's brain tissue and ascertain whether the subject had Alzheimer's or any other form of dementia. However, due to the non-feasibility of such methods, to diagnose and conclude the conditions, medical practitioners use tests that examine a patient's mental ability.
OBJECTIVE
Accurate diagnosis at an early stage is the need of the hour for initiation of therapy. The cause for most Alzheimer's cases still remains unknown except where genetic distinctions have been observed. Thus, a standard drug regimen ensues in every Alzheimer's patient, irrespective of the cause, which may not always be beneficial in halting or reversing the disease progression. To provide a better life to such patients by suppressing existing symptoms, early diagnosis, curative therapy, site-specific delivery of drugs, and application of hyphenated methods like artificial intelligence need to be brought into the main field of Alzheimer's therapeutics.
METHODS
In this review, we have compiled existing hypotheses to explain the cause of the disease, and highlighted gene therapy, immunotherapy, peptidomimetics, metal chelators, probiotics and quantum dots as advancements in the existing strategies to manage Alzheimer's.
CONCLUSION
Biomarkers, brain-imaging, and theranostics, along with artificial intelligence, are understood to be the future of the management of Alzheimer's.
Topics: Alzheimer Disease; Animals; Biomarkers; Brain; Disease Progression; Early Diagnosis; Humans; Neuroimaging
PubMed: 32484110
DOI: 10.2174/1570159X18666200528142429 -
Journal of the International... Oct 2017Although dementia has been described in ancient texts over many centuries (e.g., "Be kind to your father, even if his mind fail him." - Old Testament: Sirach 3:12), our... (Review)
Review
Although dementia has been described in ancient texts over many centuries (e.g., "Be kind to your father, even if his mind fail him." - Old Testament: Sirach 3:12), our knowledge of its underlying causes is little more than a century old. Alzheimer published his now famous case study only 110 years ago, and our modern understanding of the disease that bears his name, and its neuropsychological consequences, really only began to accelerate in the 1980s. Since then we have witnessed an explosion of basic and translational research into the causes, characterizations, and possible treatments for Alzheimer's disease (AD) and other dementias. We review this lineage of work beginning with Alzheimer's own writings and drawings, then jump to the modern era beginning in the 1970s and early 1980s and provide a sampling of neuropsychological and other contextual work from each ensuing decade. During the 1980s our field began its foundational studies of profiling the neuropsychological deficits associated with AD and its differentiation from other dementias (e.g., cortical vs. subcortical dementias). The 1990s continued these efforts and began to identify the specific cognitive mechanisms affected by various neuropathologic substrates. The 2000s ushered in a focus on the study of prodromal stages of neurodegenerative disease before the full-blown dementia syndrome (i.e., mild cognitive impairment). The current decade has seen the rise of imaging and other biomarkers to characterize preclinical disease before the development of significant cognitive decline. Finally, we suggest future directions and predictions for dementia-related research and potential therapeutic interventions. (JINS, 2017, 23, 818-831).
Topics: Alzheimer Disease; Cognitive Dysfunction; History, 20th Century; History, 21st Century; Humans; Neuropsychological Tests
PubMed: 29198280
DOI: 10.1017/S135561771700100X -
International Journal of Nanomedicine 2019Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of... (Review)
Review
Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in cortical and limbic areas of the human brain. It is characterized by memory loss and progressive neurocognitive dysfunction. The anomalous processing of APP by β-secretases and γ-secretases leads to production of Aβ and Aβ monomers, which further oligomerize and aggregate into senile plaques. The disease also intensifies through infectious agents like HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aβ peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity of Aβ, microglia get activated, endocytose Aβ, and contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against the aggregation. In addition to a detailed report on causative factors leading to AD, the present review also discusses the current state of the art in AD therapeutics and diagnostics, including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology as an efficient therapeutic strategy to increase the bioavailability of drugs in the central nervous system.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Epigenesis, Genetic; Humans; Nanotechnology; Plaque, Amyloid
PubMed: 31410002
DOI: 10.2147/IJN.S200490 -
Nature Reviews. Disease Primers May 2021Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic... (Review)
Review
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Cognitive Dysfunction; Humans; Neurodegenerative Diseases; Neurofibrillary Tangles
PubMed: 33986301
DOI: 10.1038/s41572-021-00269-y -
Journal of Alzheimer's Disease : JAD 2019Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed,... (Review)
Review
Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed, especially Alzheimer's disease (AD) and cerebrovascular ischemic disease (CVID), rather than pure AD. While these could be just two frequent unrelated comorbidities in the elderly, epidemiological research has reinforced the idea that mid-life (age <65 years) vascular risk factors increase the risk of late-onset (age ≥ 65 years) dementia, and specifically AD. By contrast, healthy lifestyle choices such as leisure activities, physical exercise, and Mediterranean diet are considered protective against AD. Remarkably, several large population-based longitudinal epidemiological studies have recently indicated that the incidence and prevalence of dementia might be decreasing in Western countries. Although it remains unclear whether these positive trends are attributable to neuropathologically definite AD versus CVID, based on these epidemiological data it has been estimated that a sizable proportion of AD cases could be preventable. In this review, we discuss the current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies, and analyze the opportunities for therapeutic and preventative interventions.
Topics: Alzheimer Disease; Genetic Predisposition to Disease; Humans; Prevalence; Risk Factors
PubMed: 30776012
DOI: 10.3233/JAD181028 -
The Lancet. Neurology Jan 2021The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE ε2 allele the strongest genetic protective factor after... (Review)
Review
The APOE ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE ε2 allele the strongest genetic protective factor after multiple large scale genome-wide association studies and genome-wide association meta-analyses. However, no therapies directed at APOE are currently available. Although initial studies causally linked APOE with amyloid-β peptide aggregation and clearance, over the past 5 years our understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption. Because all these pathological processes can potentially contribute to cognitive impairment, it is important to use this new knowledge to develop therapies directed at APOE. Several therapeutic approaches have been successful in mouse models expressing human APOE alleles, including increasing or reducing APOE levels, enhancing its lipidation, blocking the interactions between APOE and amyloid-β peptide, and genetically switching APOE4 to APOE3 or APOE2 isoforms, but translation to human clinical trials has proven challenging.
Topics: Alzheimer Disease; Animals; Apolipoproteins E; Genetic Therapy; Humans
PubMed: 33340485
DOI: 10.1016/S1474-4422(20)30412-9 -
The Medical Clinics of North America Mar 2019Alzheimer's disease (AD) care requires timely diagnosis and multidisciplinary management. Evaluation involves structured patient and caregiver history and... (Review)
Review
Alzheimer's disease (AD) care requires timely diagnosis and multidisciplinary management. Evaluation involves structured patient and caregiver history and symptom-function reviews, examination, and testing (laboratory and neuroimaging) to delineate impairment level, determine the cognitive-behavioral syndrome, and diagnose cause. Clinical biomarkers are available to aid high confidence in etiologic diagnosis. Management uses psychoeducation, shared goal setting, and patient-caregiver dyad decision making. When combined, pharmacologic and nonpharmacologic therapies mitigate symptoms and reduce clinical progression and care burden. AD biopathologic processes develop over decades before symptoms manifest; this period is increasingly targeted in research as an opportunity to best delay or prevent AD dementia.
Topics: Alzheimer Disease; Biomarkers; Diagnosis, Differential; Disease Progression; Humans; Neuroimaging; Parkinson Disease
PubMed: 30704681
DOI: 10.1016/j.mcna.2018.10.009 -
F1000Research 2018Alzheimer's disease is the most common cause of dementia worldwide, with the prevalence continuing to grow in part because of the aging world population. This... (Review)
Review
Alzheimer's disease is the most common cause of dementia worldwide, with the prevalence continuing to grow in part because of the aging world population. This neurodegenerative disease process is characterized classically by two hallmark pathologies: β-amyloid plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. Diagnosis is based upon clinical presentation fulfilling several criteria as well as fluid and imaging biomarkers. Treatment is currently targeted toward symptomatic therapy, although trials are underway that aim to reduce the production and overall burden of pathology within the brain. Here, we discuss recent advances in our understanding of the clinical evaluation and treatment of Alzheimer's disease, with updates regarding clinical trials still in progress.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Nerve Net; tau Proteins
PubMed: 30135715
DOI: 10.12688/f1000research.14506.1