Jul 2026· Pharmacology and Therapeutics· Vol 286, pp.
109084
· 1 citation· 256 references
Medicine
TL;DR
Recent advances in neurotheranostic approaches for AD are summarized and emerging molecular probes, low-molecular-weight compounds, and delivery technologies are highlighted, including contributions from the authors' studies.
Abstract
In Alzheimer's disease (AD), pathological changes start decades before symptoms appear; by the time cognitive issues are noticeable, widespread neuronal and glial dysfunction and significant neuronal loss have already occurred. Recent regulatory approvals of monoclonal antibodies targeting aggregated amyloid-β (Aβ) species, including oligomers and fibrils, represent a major advance in disease-modifying therapy. However, therapeutic efficacy is strongly dependent on intervention at the earliest pathological stages, underscoring the importance of early diagnosis and treatment. Early diagnosis requires biomarkers that accurately reflect the initiation and progression of AD pathology as well as the development of methodologies capable of capturing these pathological states in vivo. Effective early treatment necessitates strategies that suppress the formation, activation, or toxicity of molecules that trigger downstream neurodegenerative cascades, thereby interrupting disease progression at its source. In parallel, advances in targeted brain delivery technologies are essential to enable sensitive detection and effective therapeutic modulation of central nervous system targets. Neurotheranostics is an integrated conceptual framework that aims to achieve early diagnosis and targeted therapy either simultaneously or in a coordinated manner using shared molecular targets and biological readouts. By unifying molecular imaging, biomarker analysis, and disease-modifying intervention, neurotheranostics aims to overcome the limitations of conventional diagnostic and therapeutic paradigms in neurodegenerative disorders, including AD. In this review, we summarize recent advances in neurotheranostic approaches for AD and highlight emerging molecular probes, low-molecular-weight compounds, and delivery technologies, including contributions from our studies.
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.
Lalit Parihar, A. Singh, Sanjar Alam· Current Pharmacogenomics and...· 0 citations
This review summarizes the major causes of neurodegeneration, recent developments in advanced cell-based in vitro models, and commonly employed neuroprotective assays, highlighting their importance in the discovery of novel therapeutic agents for neurodegenerative diseases.
D.A. Helen Sheeba, Jayashree R, Janani K et al.· International Journal of Res...· 0 citations
Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit.
BACKGROUND
Alzheimer's disease (AD) is a significant global health challenge characterized as a multifactorial neurodegenerative disorder, involving amyloid-β (Aβ) and Tau aggregation, neuroinflammation and progressive neuronal injury. While Amyloid-targeted therapies have achieved a breakthrough in prevention of Aβ aggregation, the strategies face notable limitations in achieving curative outcomes and management of amyloid-independent central nervous system (CNS) dysfunction. Consequently, targeting microglia, the central immune cells of the brain, has emerged as a promising strategy to enhance the specificity and efficacy of AD interventions.
MAIN BODY
Accumulating evidence indicates microglial dysfunction is not a passive immune bystander of AD, but serves as a critical mechanistic nexus linking Aβ accumulation and AD symptomatic phenotype. This review critically examines the "next generation" of microglial therapeutics, moving beyond broad immunosuppression to precision phenotype modulation. We highlight breakthrough strategies in recent years including immune reconstitution, metabolic reprogramming, nanomaterial-mediated drug delivery, and the revolutionary potential of iPSC-derived microglia replacement. By elucidating the rationale underlying the specific strategies based on microglial biofunction and potential molecular mechanism in AD pathology, we provide an overview of current development of clinical trials and cutting-edge modalities aimed at restoring microglial homeostasis, affording an opportunity to alter the AD trajectory.
CONCLUSION
This review aims to delineate the path from bench to bedside and propose promising pathways to overcome current bottlenecks in AD drug development.
The dual and stage‐dependent roles of microglia and astrocytes are explored, discussion of blood–brain barrier dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors are expanded, and emerging evidence linking neuroinflammation specifically to tau pathology is integrated.
S. Papelian· International Journal of Dev...· 0 citations
"Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, primarily caused by the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain". Current therapeutic strategies focus on symptomatic relief, with acetylcholinesterase (AChE) inhibitors being a mainstay in treatment. However, the efficacy of these inhibitors is limited by their poor "bioavailability and inability to effectively cross the blood-brain barrier (BBB)". "Recent advances in nanotechnology have shown promise in overcoming these challenges through the development of nanoparticle-mediated delivery systems". These systems offer enhanced drug stability, targeted delivery, and controlled release, potentially improving the therapeutic outcomes for AD patients. This study explores the formulation of nanoparticle-based delivery systems for AChE inhibitors, evaluating their physicochemical properties, BBB permeability, and therapeutic efficacy. The include optimizing nanoparticle "size, surface charge, and composition to enhance BBB" penetration and drug release profiles. "In vitro and in vivo studies are conducted to assess" the biocompatibility, neuroprotective effects, and cognitive benefits of the formulated nanoparticles. Preliminary results indicate that nanoparticle-mediated delivery significantly enhances the bioavailability and efficacy of AChE inhibitors compared to conventional delivery methods. This research contributes to the growing field of nanomedicine, providing a foundation "for the development of more effective therapeutic strategies for Alzheimer's disease". The potential of nanoparticle-mediated delivery systems to revolutionize AD treatment underscores the importance of continued innovation in this area, paving "the way for improved patient outcomes and quality of life".
Unknown authors· Journal of Health Synapse· 0 citations
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