Tau Hypothesis Research Articles

Melatonin in Alzheimer's Disease: Literature Review and Therapeutic Trials.

There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.

Demystifying the Role of Neuroinflammatory Mediators as Biomarkers for Diagnosis, Prognosis, and Treatment of Alzheimer's Disease: A Review.

Neuroinflammatory mediators play a pivotal role in the pathogenesis of Alzheimer's Disease (AD), influencing its onset, progression, and severity. The precise mechanisms behind AD are still not fully understood, leading current treatments to focus mainly on managing symptoms rather than preventing or curing the condition. The amyloid and tau hypotheses are the most widely accepted explanations for AD pathology; however, they do not completely account for the neuronal degeneration observed in AD. Growing evidence underscores the crucial role of neuroinflammation in the pathology of AD. The neuroinflammatory hypothesis presents a promising new approach to understanding the mechanisms driving AD. This review examines the importance of neuroinflammatory biomarkers in the diagnosis, prognosis, and treatment of AD. It delves into the mechanisms underlying neuroinflammation in AD, highlighting the involvement of various mediators such as cytokines, chemokines, and ROS. Additionally, this review discusses the potential of neuroinflammatory biomarkers as diagnostic tools, prognostic indicators, and therapeutic targets for AD management. By understanding the intricate interplay between neuroinflammation and AD pathology, this review aims to help in the development of efficient diagnostic and treatment plans to fight this debilitating neurological condition. Furthermore, it elaborates recent advancements in neuroimaging techniques and biofluid analysis for the identification and monitoring of neuroinflammatory biomarkers in AD patients.

Potential Mechanisms of Tunneling Nanotube Formation and Their Role in Pathology Spread in Alzheimer's Disease and Other Proteinopathies.

Alzheimer's disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies.

Recent Advances of Mitochondrial Alterations in Alzheimer's Disease: A Perspective of Mitochondrial Basic Events.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations- bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission- fusion dynamics, mitochondrial degradation, and mitochondrial movement- underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis.

Alzheimer's Disease Pathology and Assistive Nanotheranostic Approaches for Its Therapeutic Interventions.

Alzheimer's disease (AD) still prevails and continues to increase indiscriminately throughout the 21st century, and is thus responsible for the depreciating quality of health and associated sectors. AD is a progressive neurodegenerative disorder marked by a significant amassment of beta-amyloid plaques and neurofibrillary tangles near the hippocampus, leading to the consequent loss of cognitive abilities. Conventionally, amyloid and tau hypotheses have been established as the most prominent in providing detailed insight into the disease pathogenesis and revealing the associative biomarkers intricately involved in AD progression. Nanotheranostic deliberates rational thought toward designing efficacious nanosystems and strategic endeavors for AD diagnosis and therapeutic implications. The exceeding advancements in this field enable the scientific community to envisage and conceptualize pharmacokinetic monitoring of the drug, sustained and targeted drug delivery responses, fabrication of anti-amyloid therapeutics, and enhanced accumulation of the targeted drug across the blood-brain barrier (BBB), thus giving an optimistic approach towards personalized and precision medicine. Current methods idealized on the design and bioengineering of an array of nanoparticulate systems offer higher affinity towards neurocapillary endothelial cells and the BBB. They have recently attracted intriguing attention to the early diagnostic and therapeutic measures taken to manage the progression of the disease. In this article, we tend to furnish a comprehensive outlook, the detailed mechanism of conventional AD pathogenesis, and new findings. We also summarize the shortcomings in diagnostic, prognostic, and therapeutic approaches undertaken to alleviate AD, thus providing a unique window towards nanotheranostic advancements without disregarding potential drawbacks, side effects, and safety concerns.

Beyond amyloid and tau: rethinking Alzheimer's disease through less explored avenues.

Neurodegenerative diseases, particularly Alzheimer's disease (AD), pose a significant challenge in ageing populations. Our current understanding indicates that the onset of toxic amyloid and tau protein pathologies initiates disease progression. However, existing treatments targeting these hallmark symptoms offer symptomatic relief without halting disease advancement. This review offers an alternative perspective on AD, centring on impaired adult hippocampal neurogenesis (AHN) as a potential early aetiological factor. By delving into the intricate molecular events during the initial stages of AD (Braak Stages I-III), a novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered HS sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.

Curcumin-derived carbon quantum dots: Dual actions in mitigating tau hyperphosphorylation and amyloid beta aggregation

The amyloid cascade and tau hypotheses both hold significant implications for the pathogenesis of Alzheimer's disease (AD). Curcumin shows potential by inhibiting the aggregation of amyloid beta (Aβ) and reducing tau hyperphosphorylation, however, its use is limited due to issues with solubility and bioavailability. Carbon dots, recognized for their high biocompatibility and optimal water solubility, have demonstrated the capability to inhibit either Aβ or tau aggregation. Nonetheless, their effects on tau hyperphosphorylation are yet to be extensively explored. This study aims to evaluate the water-soluble curcumin-derived carbon quantum dots (Cur-CQDs) synthesized via an eco-friendly method, designed to preserve the beneficial effects of curcumin while overcoming solubility challenges. The synthesis of Cur-CQDs involves a single-step dry heating process using curcumin, resulting in dots that exhibit negligible cytotoxicity to SH-SY5Y cells at the examined concentrations. Notably, Cur-CQDs have shown the ability to simultaneously mitigate Aβ aggregation and tau hyperphosphorylation. Therefore, it is suggested that Cur-CQDs may hold potential for AD treatment, a hypothesis deserving of further research.

Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer's Disease.

Alzheimer's disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer's disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified.

Time Factor Hypothesis: Towards Identifying Onset of Alzheimer’s Disease in Younger Adults

Introduction: Several hypotheses explain the onset and pathology of Alzheimer’s disease (AD), such as the amyloid hypothesis and the tau hypothesis. Consequently, various biomarkers have been identified and drugs developed, but the fight against the AD epidemic is still ongoing. Perhaps it is time to explore new hypotheses. To begin with, researchers have shown that neuropathology associated with AD typically starts to develop decades before the clinical onset or manifestation of the disease. However, therapeutic interventions are still being designed to address mild-to-moderate stages of the disease, which are unfortunately irreversible. Methods: We have reviewed various mathematical models to identify any missing parameters that could support the proposed time factor hypothesis for AD. In addition, we have developed a cognitive function algorithm that utilizes the identified parameters. The algorithm’s results are used to predict the likelihood of neuritic dystrophy. Results: With mathematical evidence, we emphasize the importance of timely diagnosis of AD and provide support for considering an earlier age of 30 years (rather than 60 years or older) for effective interventions, including diagnosis and drug development. Discussion: Among other points, we showed that Aβ42 aggregation starts around age 30–40 years. With this information, we propose the need to re-engineer the concepts behind the science of AD. The number of AD patients will experience a nose dive if effort aimed at timely prevention of (for instance) Aβ42 aggregation is expended.

In silico identification of colchicine derivatives as novel and potential inhibitors based on molecular docking and dynamic simulations targeting multifactorial drug targets involved in Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, characterized by a gradual and steady deterioration in cognitive function over time. At least 50 million people worldwide are considered to have AD or another form of dementia. AD is marked by a gradual decline in cognitive abilities, memory deterioration and neurodegenerative transformations within the brain. The intricate and multifaceted nature of polygenic AD presents significant challenges within the landscape of drug development. The pathophysiology of AD unfolds in a non-linear and dynamic pattern, encompassing various systems and giving rise to a multitude of factors and hypotheses that contribute to the disease’s onset. These encompass theories such as the beta-amyloid hypothesis, cholinergic hypothesis, tau hypothesis, oxidative stress and more. In the realm of drug development, polypharmacological drug profiles have emerged as a strategy that can yield combined or synergistic effects, effectively mitigating undesirable side effects and significantly enhancing the therapeutic efficacy of essential medications. With this concept in mind, our in-silico study sought to delve into the binding interactions of a diverse array of colchicine derivative compounds. These derivatives are chosen for their potential anti-inflammatory, antioxidant, anti-neurodegenerative and neuroprotective properties against Alzheimer’s and other neurodegenerative diseases. We investigated compound interactions with AD-related targets, utilizing comprehensive molecular docking and dynamic simulations. COM111X showed impressive docking with acetylcholinesterase, indicating potential as an anti-Alzheimer’s drug. COM112Y displayed strong docking scores with PDE4D and butyrylcholinesterase, suggesting dual inhibition for Alzheimer’s treatment. Further in vitro and in vivo studies are warranted to explore these findings. Communicated by Ramaswamy H. Sarma

Pathogenesis of Alzheimer's Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential.

Alzheimer's disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer's disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer's agents. The review will provide (A) precise insight of various established targets of Alzheimer's disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure-activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer's agents. This review will provide a baseline for various research groups working on Alzheimer's drug development in designing potent, safer, and effective multifunctional anti-Alzheimer's candidates of the future.

The tau hypothesis of nodding syndrome in Africa.

The tau hypothesis of nodding syndrome in Africa.

Mechanism and treatment of cell death in Alzheimer's disease

With 60 to 80% of cases, Alzheimer's disease (AD) is the primary trigger of dementia around the globe. The prevalence of people aged 65-69 years increased from 1% to about 30% of people aged 85 years, resulting in more than 50 million affected individuals globally. The AD in the formation of amyloid, the tau protein distribution, the interaction between amyloid and tau protein, clinical symptoms, the genetic background and so on various aspects are heterogeneity exists. Therefore, there is no single pathological process or mechanism of action that can explain why people develop AD. The prevalence of Alzheimer's disease is one of the largest global public health issues today. There have been many different therapy modalities investigated over time. But there is still no cure, and all that can be done for AD is to prevent and delay its progression. Current drug treatments are intended only to alleviate symptoms, not cure the root cause. Based on the universalization and decreasing age of AD, it is particularly significant to study the causes and pathogenesis of AD and how to prevent and treat it. This paper introduces the main stages of the process of AD, introduces two hypotheses -- tau hypothesis and amyloid interpretation，and the role of RNA splicing in this process is summarized. In addition, in order to provide more research ideas, the author describes the current treatment options for AD, from the risk factors that may cause AD to the latest specific treatments. The treatment approach suggests that both at-risk patients and those without underlying diseases make early lifestyle and dietary adjustments and gradually move towards a healthy lifestyle in order to reduce the incidence of Alzheimer's and the financial burden on families and society. This is in addition to early drug treatment to lessen the suffering and life experience of Alzheimer's patients.

An ongoing journey of chalcone analogues as single and multi-target ligands in the field of Alzheimer's disease: A review with structural aspects.

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disorder with progressive dementia and cognitive impairment. AD poses severe health challenge in elderly people and become one of the leading causes of death worldwide. It possesses complex pathophysiology with several hypotheses (cholinergic hypothesis, amyloid hypothesis, tau hypothesis, oxidative stress, mitochondrial dysfunction etc.). Several attempts have been made for the management of multifactorial AD. Acetylcholinesterase is the only target has been widely explored in the management of AD to the date. The current review set forth the chalcone based natural, semi-synthetic and synthetic compounds in the search of potential anti-Alzheimer's agents. The main highlights of current review emphasizes on chalcone target different enzymes and pathways like Acetylcholinesterase, β-secretase (BACE1), tau proteins, MAO, free radicals, Advanced glycation end Products (AGEs) etc. and their structure activity relationships contributing in the inhibition of above mentioned various targets of AD.

A Study of HDAC6 for Ameliorating the Cognitive Function in Alzheimer's Disease

One of the most prevalent causes of dementia, Alzheimer's disease (AD) is characterized by gradual mental decline and memory loss over time. Several drugs are currently available for the treatment of AD, but they only address the disease's symptoms rather than its underlying pathogenesis. Researchers looked into epigenetic therapy and found that histone deacetylase 6 (HDAC6) could be an effective treatment for Alzheimer's disease. This paper uses a literature review approach to investigate the roles of HDAC6 inhibition in AD models and HDAC6 inhibitors, as well as the hypotheses surrounding the pathogenesis of AD. The amyloid cascade hypothesis, the tau hypothesis, and the role of oxygen species are identified as the most prominent pathogenesis hypotheses in this paper. A decrease in Hdac6 levels improves associative and spatial memory in an Alzheimer's disease mouse model and reverses the mitochondrial trafficking impairment in hippocampal neurons in vitro and in vivo. Therefore, inhibiting HDAC6 may represent a novel approach to treating AD-related cognitive decline. As a result of these issues, the FDA has yet to approve any HDAC6 inhibitor for use in the treatment of Alzheimer's disease (FDA)

The role of human serum albumin in prevention and treatment of Alzheimer’s disease

Alzheimer’s disease (AD) has been and remains the main cause of dementia in aging patients. This neurodegenerative disease belongs to the progressive and socially significant ones. There are several hypotheses for the development of AD: the tau hypothesis, the amyloid cause, the cholinergic cause, the cause of oxidative stress and inflammation. The lack of a generally accepted understanding of the etiology and pathogenesis of AD hinders the development of new effective mechanisms for its treatment and prevention. In 2021, for the first time, a drug for pathogenetic therapy of AD (aducanumab) was approved, which helps to reduce the content of amyloid-β peptide (Aβ) in the brain of patients. Another promising approach to the treatment of AD, aimed at removing Aβ from the patient’s central nervous system, is the impact on human serum albumin (HSA), which carries 90% of Aβ in the blood serum and 40–90% of Aβ in the cerebrospinal fluid. In clinical practice, plasmapheresis has already been tested and shown to be effective with the replacement of one’s own HSA with a purified therapeutic albumin preparation. Another variant of this approach is to enhance the interaction of HSA with Aβ through the action of exogenous and endogenous HSA ligands, such as serotonin, ibuprofen and some unsaturated fatty acids. In vivo studies confirm the association of this group of ligands with the pathogenesis of AD. These substances are well-studied natural metabolites or drugs, which greatly simplifies the development of new methods of therapy and prevention of AD with their use. In general, a new direction of scientific research devoted to the study of HSA as a carrier and depot of Aβ in the blood and cerebrospinal fluid will expand our understanding of Aβ metabolism and its role in the pathogenesis of AD.

Evaluation of Pathological Perspectives Related to Alzheimers Disease

Alzheimers disease (AD), one of the degenerative diseases and dementias, caused more than millions of people to suffer from it. Over the past few decades, scientists have been putting much effort to study this particular disease in the hope of finding the drug to cure AD. In this condition, two significant hallmarks were discovered, senile plaques and neurofibrillary tangles (NFTs), furthermore leads scientists to focus on A and tau protein to study the pathogenesis of AD. However, the real culprit contributing to AD still remains unknown. Although many amyloid-targeted drugs and tau-targeted drugs are developed, they all failed, causing scientists to cast doubt on the amyloid-related perspective and tau-related perspective. This article will mainly discuss the amyloid hypothesis and the tau hypothesis, the factors driving the formation of senile plaques and NFTs, the scientific data supporting and opposing these two perspectives, the criticisms they are facing, and most importantly the future orientation for scientists to study. Here, after understanding the amyloid-related perspective, tau-related perspective, and other perspectives proposed for AD, we extrapolate that the pathogenesis of AD is multifactorial; moreover, the future AD study should take multiple factors into account.

A Review on Garlic as a Supplement for Alzheimer’s Disease: A Mechanistic Insight into its Direct and Indirect Effects

Alzheimer’s disease (AD) is one of the most complicated neurodegenerative diseases causing dementia in human beings. Aside from that, the incidence of AD is increasing and its treatment is very complicated. There are several known hypotheses regarding the pathology of Alzheimer’s disease, including the amyloid beta hypothesis, tau hypothesis, inflammation hypothesis, and cholinergic hypothesis, which are investigated in different researches to completely elucidate the pathology of AD. Besides, some new mechanisms, such as immune, endocrine, and vagus pathways, as well as bacteria metabolite secretions, are being explained as other causes to be somehow related to AD pathogenesis. There is still no definite treatment for Alzheimer’s disease that can completely cure and eradicate AD. Garlic (Allium sativum) is a traditional herb used as a spice in different cultures, and due to the organosulfur compounds, like allicin, it possesses highly anti-oxidant properties; the benefits of garlic in cardiovascular diseases, like hypertension and atherosclerosis, have been examined and reviewed, although its beneficiary effects in neurodegenerative diseases, such as AD, are not completely understood. In this review, we discuss the effects of garlic based on its components, such as allicin and S-allyl cysteine, on Alzheimer’s disease and the mechanisms of garlic components that can be beneficiary for AD patients, including its effects on amyloid beta, oxidative stress, tau protein, gene expression, and cholinesterase enzymes. Based on the literature review, garlic has been revealed to have beneficiary effects on Alzheimer’s disease, especially in animal studies; however, more studies should be done on humans to find the exact mechanisms of garlic’s effects on AD patients.

Molecular mechanisms of amyloid-β peptide fibril and oligomer formation: NMR-based challenges.

To completely treat and ultimately prevent dementia, it is essential to elucidate its pathogenic mechanisms in detail. There are two major hypotheses for the pathogenesis of Alzheimer's dementia: the β-amyloid (Aβ) hypothesis and the tau hypothesis. The modified amyloid hypothesis, which proposes that toxic oligomers rather than amyloid fibrils are the essential cause, has recently emerged. Aβ peptides [Aβ(1-40) and Aβ(1-42)] form highly insoluble aggregates in vivo and in vitro. These Aβ aggregates contain many polymorphisms, whereas Aβ peptides are intrinsically disordered in physiological aqueous solutions without any compact conformers. Over the last three decades, solid-state nuclear magnetic resonance (NMR) has greatly contributed to elucidating the structure of each polymorph, while solution NMR has revealed the dynamic nature of the transient conformations of the monomer. Moreover, several methods to investigate the aggregation process based on the observation of magnetization saturation transfer have also been developed. The complementary use of NMR methods with cryo-electron microscopy, which has rapidly matured, is expected to clarify the relationship between the amyloid and molecular pathology of Alzheimer's dementia in the near future. This review article is an extended version of the Japanese article, Insights into the Mechanisms of Oligomerization/Fibrilization of Amyloid β Peptide from Nuclear Magnetic Resonance, published in SEIBUTSU BUTSURI Vol. 62, p. 39-42 (2022).

Chapter 10 - Finding the falsification threshold of the toxic proteinopathy hypothesis in neurodegeneration

A biomedical hypothesis is a theoretical assumption amenable to being tested in a randomized clinical trial. The main hypotheses in neurodegenerative disorders are based on the concept that proteins accumulate in an aggregated fashion and trigger toxicity. The toxic proteinopathy hypothesis posits that neurodegeneration is caused by toxicity of aggregated amyloid in Alzheimer's disease (toxic amyloid hypothesis), aggregated α-synuclein in Parkinson's disease (toxic synuclein hypothesis), and aggregated tau in progressive supranuclear palsy (toxic tau hypothesis). To date, we have accumulated 40 negative anti-amyloid randomized clinical, 2 anti-synuclein trials, and 4 anti-tau trials. These results have not prompted a major reconsideration of the toxic proteinopathy hypothesis of causality. Imperfections in trial design and execution (incorrect dosage, insensitive endpoints, too-advanced population) but not in the underlying hypotheses have prevailed as explaining the failures. We review here the evidence suggesting that the threshold of hypothesis falsifiability may be too high and advocate in favor of a minimal set of rules that facilitate the interpretation of negative clinical trials as falsifying the driving hypotheses, in particular if the desirable change in surrogate endpoints has been achieved. We propose four steps to refute a hypothesis in future-negative surrogate-backed trials and argue that for the actual rejection to take place, refutation must be accompanied by the proposal of an alternative hypothesis. The absence of alternative hypotheses may be the single greatest reason why there remains hesitancy in rejecting the toxic proteinopathy hypothesis: in the absence of alternatives, we have no clear guidance as to where to redirect or focus.