Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease that inevitably results in dementia and death. Currently, there are no pathogenetically grounded methods for the prevention and treatment of AD, and all current treatment regimens are symptomatic and unable to significantly delay the development of dementia. The accumulation of β-amyloid peptide (Aβ), which is a spontaneous, aggregation-prone, and neurotoxic product of the processing of signaling protein APP (Amyloid Precursor Protein), in brain tissues, primarily in the hippocampus and the frontal cortex, was for a long time considered the main cause of neurodegenerative changes in AD. However, attempts to treat AD based on decreasing Aβ production and aggregation did not bring significant clinical results. More and more arguments are arising in favor of the fact that the overproduction of Aβ in most cases of AD is not the initial cause, but a concomitant event of pathological processes in the course of the development of sporadic AD. The concept of neuroinflammation has come to the fore, suggesting that inflammatory responses play the leading role in the initiation and development of AD, both in brain tissue and in the periphery. The hypothesis about the key role of neuroinflammation in the pathogenesis of AD opens up new opportunities in the search for ways to treat and prevent this socially significant disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia globally. The pathogenesis of AD remains still unclear. The three main features of AD are extracellular deposits of amyloid beta (Aβ) plaque, accumulation of abnormal formation hyper-phosphorylated tau protein, and neuronal loss. Mitochondrial impairment plays an important role in the pathogenesis of AD. There are problems with decreased activity of multiple complexes, disturbed mitochondrial fusion, and fission or formation of reactive oxygen species (ROS). Moreover, mitochondrial transport is impaired in AD. Mouse models in many research show disruptions in anterograde and retrograde transport. Both mitochondrial transportation and network impairment have a huge impact on synapse loss and, as a result, cognitive impairment. One of the very serious problems in AD is also disruption of insulin signaling which impairs mitochondrial Aβ removal.Discovering precise mechanisms leading to AD enables us to find new treatment possibilities. Recent studies indicate the positive influence of metformin or antioxidants such as MitoQ, SS-31, SkQ, MitoApo, MitoTEMPO, and MitoVitE on mitochondrial functioning and hence prevent cognitive decline. Impairments in mitochondrial fission may be treated with mitochondrial division inhibitor-1 or ceramide.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

Despite decades of research, Alzheimer’s disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy–lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions.

Monoclonal antibody (mAb) therapies targeting amyloid-beta (Aβ) plaques have gained prominence over the past decade as potential disease-modifying treatments for Alzheimer's disease (AD), leading to major regulatory approvals and global debate. Nonetheless, the central question persists: does this emerging therapy have a justified role in the treatment protocol for AD? This systematic review evaluates the efficacy and safety of these agents across phase II and III clinical trials conducted in the past decade (2014-2024), aligning with the timeline when disease-modifying therapies gained momentum. A systematic search was performed across PubMed and the Cochrane Library to identify phase II and III randomized controlled trials (RCTs) conducted between January 2014 and December 2024. The inclusion criteria focused on studies that evaluated cognitive outcomes using scales such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Mini-Mental State Examination (MMSE). Additionally, trials assessing biomarkers, including CSF measures and PET imaging, were included. Safety outcomes, particularly amyloid-related imaging abnormalities (ARIA), were also systematically analyzed. Due to heterogeneity in outcome measures, a narrative synthesis was conducted. Sixteen RCTs met the inclusion criteria. Lecanemab reduced amyloid burden with 81% of patients achieving amyloid-negative PET scans (Clarity AD trial) and showed a 27% reduction in cognitive decline on the ADCOMS scale. While statistically significant, the 27% ADCOMS (Alzheimer's Disease Composite Score) reduction warrants comparison to MCID (minimal clinically important difference) thresholds (e.g., ~0.5-1.0 points for CDR-SB in early AD) to assess real-world impact. Donanemab demonstrated 76% plaque clearance and a 35% slowing in cognitive decline in early AD patients. Aducanumab showed dose-dependent effects on plaque clearance but had inconsistent cognitive outcomes and higher ARIA rates. Recent mAb trials provide promising evidence for disease modification in early AD stages, particularly with lecanemab and donanemab. However, variability in cognitive outcomes and safety concerns warrant cautious interpretation and long-term validation.

The article analyzes contemporary literature data on standard and alternative therapeutic methods for Alzheimer's disease (AD). The main approaches currently include the use of cholinesterase inhibitors and NMDA receptor antagonists, which help slow disease progression and improve patients' quality of life. Due to their insufficient effectiveness, there is a search for new treatment methods based on the connection between AD and other conditions. This article will examine the cross-mechanisms of pathogenesis linking type 2 diabetes and AD, as well as analyze new therapeutic approaches, including intranasal insulin administration and the use of insulin sensitizers. Neurodegenerative processes, including AD, are based on a violation of intracellular calcium metabolism, which suggested the potential efficiency of calcium channel blocker drugs currently used in the treatment of arterial hypertension. Key hypotheses regarding the pathogenesis of AD include the amyloid hypothesis, based on the accumulation of beta-amyloid, and the tau hypothesis, related to hyperphosphorylated tau protein aggregation. Alternative mechanisms such as neuroinflammation are also discussed. In this context, an innovative method for treating AD is immunotherapy, aimed at eliminating beta-amyloid that causes neurodegeneration. Thus, the necessity for integrating various hypotheses for a more comprehensive understanding of pathology and developing effective therapeutic strategies is emphasized. The article

There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.

Alzheimer's disease (AD) is a complex disease of the brain. Despite over 100 years of basic and clinical research, significantly intensified in the last three decades, the exact cause of this neurodegeneration is still an enigma. Based on neuroanatomical, experimental, and clinical findings, a series of hypotheses on AD pathogenesis have evolved. Among them, the "amyloid cascade hypothesis" has been most prominent. Clinical efforts targeting the biochemistry of amyloid β-protein (Aβ) as causal therapy have all failed so far, which may mean that the pathogenic mechanism of AD is less straightforward than initially thought. While there was good scientific reason to support this hypothesis before, the exclusive concentration on it may have impeded a more objective look and prevented the pursuit of alternative approaches to decipher the cause of AD. Here, a few key hypotheses of AD are summarized, and it is proposed that our view of the cause (or causes) of this detrimental disease be widened. This includes looking back, reactivating, and revisiting findings that were ignored over the last decades. Alternative and amyloid-independent ways to explain AD pathogenesis should receive more attention and are appearing.

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

For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.

<h4>Background</h4>Alzheimer's disease (AD) has been linked to impaired clearance of metabolic waste, and glymphatic dysfunction is increasingly considered a potential contributor to its pathogenesis. The diffusion tensor imaging-based analysis along the perivascular space (ALPS) index has been proposed as a non-invasive imaging marker, although findings across clinical studies remain inconsistent.<h4>Methods</h4>We systematically searched PubMed, Embase, Web of Science, Scopus, CENTRAL, and PEDro up to August 2025 in accordance with PRISMA guidelines. Studies reporting ALPS index values in adults with AD, mild cognitive impairment (MCI), or cognitively normal controls (NC) were included. Risk of bias was assessed using the AHRQ checklist, and the certainty of evidence was evaluated with GRADE.<h4>Results</h4>Fifteen studies involving 1,756 participants were included in the meta-analysis. Pooled results showed a stepwise decrease in ALPS values, with significantly lower values in AD compared with NC (mean difference -0.20, <i>I</i> ² = 93%) and MCI (-0.09, <i>I</i> ² = 78%), as well as in MCI compared with NC (-0.11, <i>I</i> ² = 92%). Subgroup and sensitivity analyses supported the stability of these findings despite methodological heterogeneity.<h4>Conclusion</h4>The ALPS index shows a progressive decrease across the AD continuum, which is consistent with the presence of glymphatic alterations during disease progression. As a non-invasive MRI-derived marker, ALPS may have potential for use in early detection and monitoring; however, further validation with standardized imaging protocols and longitudinal studies is required before clinical application.<h4>Systematic review registration</h4>https://www.crd.york.ac.uk/PROSPERO/view/CRD420251119624, PROSPERO, CRD420251119624.