Mechanisms and Intervention Strategies of Beta-Amyloid and Tau Proteins in Alzheimer's Disease

Neuropharmacological Interventions in Alzheimer’s Disease: Current and Emerging Approaches

Alzheimer’s Disease (AD) is a neurodegenerative disorder with progressive cognitive decline, β-amyloid plaques, neurofibrillary tangles, oxidative stress, and neuroinflammatory responses. So far, the pathogenesis of AD has been explained by the cholinergic hypothesis, amyloid cascade hypothesis, and tau protein dysfunction. However, the current pharmacological treatment of AD with cholinesterase inhibitors and NMDA receptor antagonists provides only symptomatic relief and cannot prevent the progression of the disease. This review article discusses the recent developments in neuropharmacology in the treatment of AD with a focus on the discovery of novel therapeutic targets and innovative therapeutic strategies with multi-target pharmacology involving protein–protein interaction inhibitors, allosteric modulators, selective enzyme inhibitors, and proteolysistargeting chimeras (PROTACs), and the discovery of novel drug delivery systems to overcome the blood–brain barrier. Current preclinical and emerging evidence indicate that the modulation of interconnected pathological pathways, including mitochondrial dysfunction, insulin resistance, and neuroinflammation, may lead to improved therapeutic outcomes. Dual inhibitors of tau hyperphosphorylation and Aβ aggregation have been shown to improve therapeutic efficacy, while modulation of neurotrophic signaling pathways, including BDNF, has been shown to possess neuroprotective effects. Moreover, improved drug delivery systems across the BBB will enhance drug bioavailability, thereby increasing therapeutic efficiency. Despite the promising preclinical data, there are several challenges in translating these therapeutic interventions into clinical success in AD treatment due to the complexity of the disease, delayed diagnosis, and lack of predictive markers. The incorporation of early diagnostic biomarkers in conjunction with the use of multi-target therapy will improve therapeutic efficacy in the treatment of AD. Neuropharmacological approaches, where various mechanisms of pathology are targeted, hold promise for developing disease-modifying treatments for AD. Further research in this area, incorporating innovative drug development techniques, drug delivery systems, and early intervention techniques, is crucial for better patient outcomes and slower disease progression.

NEW THERAPEUTIC OPPORTUNITIES IN ALZHEIMER'S DISEASE: THE ROLE OF ANTI-AMYLOID ANTIBODIES: A COMPREHENSIVE REVIEW

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuronal loss, and the accumulation of β-amyloid plaques and tau pathology. For many years, pharmacological treatment has been limited to symptomatic therapies, including acetylcholinesterase inhibitors and memantine, which provide only modest clinical benefits without modifying disease progression. The development of anti-amyloid monoclonal antibodies has introduced the first disease-modifying therapeutic approach targeting the underlying pathology of AD. Agents such as aducanumab, lecanemab, and donanemab reduce cerebral amyloid burden through selective targeting of different forms of β-amyloid. Clinical trials, including CLARITY AD and TRAILBLAZER-ALZ 2, have demonstrated that these therapies can slow cognitive decline in patients with early-stage AD, although their efficacy depends on disease stage and patient selection. Despite remaining challenges, including safety concerns and the risk of amyloid-related imaging abnormalities, anti-amyloid therapies represent a major advancement in the treatment of Alzheimer’s disease and mark a transition toward disease-modifying strategies.

Tau Protein Pathology and Tau-Targeted Therapeutic Strategies in Alzheimer’s Disease: Mechanisms, Clinical Evidence and Future Perspectives

Alzheimer's disease (AD) is the most dominant form of dementia characterized by neurodegeneration which leads to progressive cognitive decline and memory loss, the common symptoms of AD. While amyloid-β peptide accumulation has traditionally been the primary focus of AD research, there is growing evidence that tau pathology also contributes significantly in disease progression. Tau is a microtubule-associated protein that normally stabilizes microtubules and supports axonal transport within neurons. However, abnormal hyperphosphorylation causes tau to detach from microtubules, misfold and aggregate into toxic filaments which ultimately lead to neurodegeneration and eventually cell death. This paper reviews the structure of tau protein, its physiological and pathological behaviours and tau's mechanism in terms of disease progression. This paper also examines clinical and preclinical evidences and discusses the efficacy and limitations of three tau-targeted therapeutic approaches: gosuranemab, a monoclonal antibody designed to prevent the spread of extracellular tau; BIIB080, an antisense oligonucleotide that reduces tau production by targeting MAPT mRNA; and leucomethylthioninium bis (LMTM), a tau aggregation inhibitor. Studies also suggest the potential of combination therapies targeting multiple pathological pathways to enhance efficacy. Though no tau-targeted therapy has yet to demonstrate definitive clinical benefit, continued research supports tau as an important therapeutic target and contributes to the development of more effective treatments for AD.

Neuroinflammatory and molecular pathways in Alzheimer's disease: mechanistic crosstalk and emerging therapeutic opportunities.

Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.

Multimodal mechanistic pathways in Alzheimer’s disease: toward an integrated model of pathogenesis

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid plaques, tau tangles, synaptic dysfunction, and large-scale network failure. While the amyloid cascade hypothesis has dominated, emerging evidence suggests distinct yet interacting amyloid and tau trajectories influenced by genetic, vascular, metabolic, and inflammatory factors. Understanding this multimodal convergence is key to redefining AD pathogenesis. Following PRISMA 2020 guidelines, mechanistic studies published from January 2016 to August 2025 were reviewed from pubmed and the cochrane library. Eligible studies provided original data on molecular, cellular, or systems-level mechanisms of AD. Findings were synthesized across seven domains: amyloid, tau, neuroinflammation, synaptic dysfunction, mitochondrial stress, metabolic dysregulation, and genetics. Across 22 studies, evidence supports a shift from a linear amyloid model to a multidimensional framework. Amyloid and tau initiate independently but later interact to accelerate degeneration. APOE ε4 carriers show amyloid-driven disease, while non-carriers exhibit tau-dominant progression, with females showing higher vulnerability. fMRI and DTI reveal early Default Mode Network and white matter disruption. Biomarkers (Aβ42, tau, NfL, neurogranin, SNAP25) detect early changes, while mitochondrial and glial dysfunction and vascular-metabolic stress further modulate progression. AD emerges from converging genetic, molecular, and network-level abnormalities. A multimodal approach integrating imaging, fluid biomarkers, and genetics offers promise for early detection, risk stratification, and personalized multi-target therapies.

Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.