Current insights into the pathophysiology of Alzheimer's disease: selecting targets for early therapeutic intervention

2012 ◽  
Vol 24 (S1) ◽  
pp. S10-S17 ◽  
Author(s):  
Harald Hampel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Investigation ◽  
Disease Process ◽  
Predictive Biomarkers ◽  
Underlying Disease ◽  
Disease Stage ◽  
Drug Candidates ◽  
Surrogate Outcome ◽  
Models Of Disease

ABSTRACTThe development of therapies for Alzheimer's disease (AD) presents numerous challenges for physicians, researchers, and the pharmaceutical industry, with many drug candidates showing promise at one stage of clinical research only to fall at the next hurdle. A great number of drugs with a variety of targets and clusters of mechanisms are currently in various stages of basic and clinical investigation. However, these hypothesis-derived agents may be tested much too late in the chronically progressive disease process to demonstrate meaningful effects or outcomes, mirroring the clinical syndromal scenario in which the underlying pathophysiological disease condition is frequently diagnosed extremely late. Moreover, the complexity of the disease calls for developments and improvements in study designs and methods modeled for different target populations and disease stages (e.g. asymptomatic to prodromal to syndromal). New integrated concepts and models of disease pathophysiology, use of validated and qualified biomarkers, outcomes and endpoints, particularly the development of a surrogate outcome, may allow targeting of characteristic mechanism-derived therapies of specifically affected biological systems at different time-points in the disease process, providing increasing opportunities for early and preventative intervention. A core set of feasible diagnostic and predictive biomarkers is already validated and in the process of standardization; however, continued and intensified research efforts will likely reveal a variety of novel biomarkers that grasp the complexity of the underlying disease process. In the future, trials of drugs to modify and prevent AD may embrace enrichment strategies and maybe be stratified by disease stage, genetic factors as well as by disease endophenotypes.

Measuring Disease Modification in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 11-14
Author(s):  
Jeffrey L. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Pharmacological treatment of Alzheimer’s disease

2017 ◽  
Author(s):  
Krishna Chinthapalli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pharmacological Treatment ◽  
Daily Living ◽  
Disease Process ◽  
Acetylcholinesterase Inhibitors ◽  
Underlying Disease ◽  
Global Function ◽  
Glutamate Antagonist ◽  
The Brain

Pharmacological treatment of Alzheimer’s disease is an important part of management of the condition. There are only four drugs available for treatment of the disease and none halt the disease process, however they have a benefit on cognition, behaviour, activities of daily living, and global function. Acetylcholinesterase inhibitors are thought to work by enhancing cholinergic transmission in the brain and are particularly effective in mild and moderate AD, with recent evidence suggesting donepezil is also effective in severe AD. Memantine is the only glutamate antagonist that is available for AD and is limited for use in moderate or severe AD. The choice of drug depends on route of administration, adverse effects, and medical comorbidities. There is intense research on alternative treatments especially those that may stop the underlying disease process.

Introduction: Amyloid-Based Interventions in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 2-3 ◽  
Author(s):  
Gary J. Kennedy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Reductase Inhibitors ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

A Clinical Overview of Cholinesterase Inhibitors in Alzheimer's Disease

2002 ◽  
Vol 14 (S1) ◽  
pp. 93-126 ◽  
Author(s):  
Martin Farlow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Symptomatic Relief ◽  
Disease Process ◽  
Lewy Body Dementia ◽  
Underlying Disease ◽  
Research Experience ◽  
Behavioral Disturbances ◽  
The Individual ◽  
Che Inhibitors

This review provides an overview of the three most widely used cholinesterase (ChE) inhibitors: donepezil, rivastigmine, and galantamine. Differences in pharmacologic profiles will be discussed, and consideration will be given to how such differences may relate to and influence the clinical efficacy and tolerability of the various agents. In addition to providing cognitive benefits in patients with Alzheimer's disease (AD), growing clinical evidence also suggests that ChE inhibitors can produce favorable and clinically relevant effects on neuropsychiatric/behavioral disturbances and activities of daily living. Furthermore, recent data indicate that these agents may be effective at all levels of disease severity and for all rates of disease progression. The clinical utility of ChE inhibitors in a wider spectrum of dementias which share a common cholinergic deficit, such as Lewy body dementia, Parkinson's disease dementia, and vascular dementia, is currently under investigation. Beyond symptomatic relief, data suggest that ChE inhibitors may also slow the underlying disease process. As clinical and research experience with these agents continues to accumulate, the differences in their effects will become more apparent and will help physicians tailor ChE inhibition treatment to the needs of the individual patient.

The Pathogenesis of Alzheimer's Disease and the Role of Aβ42

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 4-6 ◽  
Author(s):  
Todd E. Golde
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Reductase Inhibitors ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Clinical Trials of Amyloid-Based Therapies for Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 7-10 ◽  
Author(s):  
Pierre N. Tariot
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (activeβ-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Auditory Dysfunction in Alzheimer's Disease

2010 ◽  
Vol 15 (1) ◽  
pp. 4-11 ◽  
Author(s):  
Sridhar Krishnamurti
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Health Care ◽  
Care Setting ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Clinical Protocols ◽  
Speech Language Pathologist ◽  
Auditory Dysfunction

Alzheimer's disease is neurodegenerative disorder which affects a growing number of older adults every year. With an understanding of auditory dysfunction in Alzheimer's disease, the speech-language pathologist working in the health care setting can provide better service to these individuals. The pathophysiology of the disease process in Alzheimer's disease increases the likelihood of specific types of auditory deficits as opposed to others. This article will discuss the auditory deficits in Alzheimer's disease, their implications, and the value of clinical protocols for individuals with this disease.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

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