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Pharmacotherapy for Alzheimer’s Disease, 2nd Edition
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Pharmacotherapy for Alzheimer’s Disease, 2nd Edition

A Special Issue of Pharmaceuticals (ISSN 1424-8247) belonging to the section "Pharmacology".

Deadline for manuscript submissions: 25 October 2026 | Viewed by 7224

Editor

Dr. Gabriela Dumitrița Stanciu

E-Mail Website
Guest Editor
Advanced Research and Development Center for Experimental Medicine “Prof. Ostin C. Mungiu”, “Grigore T. Popa” University of Medicine and Pharmacy of Iasi, 700115 Iasi, Romania
Interests: neuroscience; Alzheimer’s disease; in vivo studies; drug development; cannabinoid-based pharmaceuticals; repurposing current therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A large body of studies highlight that Alzheimer’s disease (AD), described as a complex neurodegenerative disorder with a multilayered nature leading to a progressive decline in cognitive function and irreversible neuronal loss, continues to present a significant and escalating challenge to global health. As the frequency of cases rises and conventional pharmaceutical treatments, which primarily alleviate symptoms and come with numerous side effects, continue to exhibit a high rate of ineffectiveness, there arises a pressing demand for alternative approaches. Despite extensive knowledge on the molecular basis of AD, advancements in developing therapies that truly modify the progression of the disease have proven to be elusive. The ability of editing system tools, repurposing current therapeutics or utilizing multi-target-directed ligands, presents a promising opportunity to elucidate the fundamental mechanisms driving AD pathogenesis and discover new therapeutic pathways. This strategy has the potential to facilitate the identification of target molecules and the development of innovative preclinical disease models, thus providing hopeful prospects for therapeutic intervention.

Authors are invited to submit original research and review articles highlighting recent findings in the pharmacotherapy of Alzheimer’s disease. These include, but are not limited to, novel molecular mechanisms and potential therapeutic targets, developing or repurposing drugs with the ability to target multiple disease features or exploring the risks and benefits of cannabinoid-based drugs.

Dr. Gabriela Dumitrița Stanciu
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • pharmacotherapy
  • therapeutic editing tools
  • repurposing existing therapeutics
  • multi-target-directed ligands
  • preclinical studies
  • neurodegeneration
  • drug development
  • neuroprotection
  • cannabinoid-based pharmaceuticals
  • single-molecule drugs or whole-plant extracts of Cannabis sativa L.

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Related Special Issue

Published Papers (5 papers)

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Research

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14 pages, 9224 KB  
Article
Ginsenoside Compound K Differentially Regulates Neuronal and Astrocytic Ca2+ Homeostasis Under Trimethyltin-Induced Stress
by Hayeong Jeon, Yoo Jin Kim and Geun Hee Seol
Pharmaceuticals 2026, 19(9), 1376; https://doi.org/10.3390/ph19091376 - 31 Aug 2026
Viewed by 170
Abstract
Background: Intracellular Ca2+ dysregulation and neurovascular dysfunction are increasingly recognized as important mechanisms underlying neurodegenerative disorders, including Alzheimer’s disease (AD). Restoration of pathological Ca2+ imbalance has therefore emerged as a potential therapeutic strategy. Although ginsenoside compound K (CK) has demonstrated [...] Read more.
Background: Intracellular Ca2+ dysregulation and neurovascular dysfunction are increasingly recognized as important mechanisms underlying neurodegenerative disorders, including Alzheimer’s disease (AD). Restoration of pathological Ca2+ imbalance has therefore emerged as a potential therapeutic strategy. Although ginsenoside compound K (CK) has demonstrated neuroprotective and anti-inflammatory properties, its role in Ca2+ homeostasis remains unclear. Methods: SH-SY5Y neuronal cells, U373 astrocytes, BV2 microglia, bEND brain endothelial cells, and MOVAS vascular smooth muscle cells were exposed to trimethyltin chloride (TMT, 5 μM, 24 h). Cell viability, real-time cell confluence, intracellular Ca2+ influx, and endoplasmic reticulum (ER) Ca2+ store release were evaluated. Ca2+ dynamics were analyzed using Fura-2 fluorescence, and signaling associated with CK-mediated Ca2+ regulation was investigated using pharmacological inhibitors. Orai1 protein expression was evaluated by Western blot analysis in SH-SY5Y and U373 cells. Results: TMT increased store-operated Ca2+ entry (SOCE)-mediated Ca2+ influx in SH-SY5Y neuronal cells without significant cytotoxicity. In contrast, TMT reduced both Ca2+ influx and cell viability in U373 astrocytes, BV2 microglia, and MOVAS cells, whereas bEND cells showed minimal changes. CK restored abnormal Ca2+ responses in a cell type-specific manner, reducing elevated Ca2+ influx in neuronal cells while restoring suppressed Ca2+ signaling in astrocytes. Consistent with these functional findings, Orai1 protein expression was increased by TMT in SH-SY5Y cells and attenuated by CK, whereas TMT reduced Orai1 expression in U373 cells, which was restored by CK. Pharmacological analyses suggested involvement of PKA- and LTCC-associated signaling in neuronal cells and PLC- and PLD-associated signaling in astrocytes. In both cell types, CK-associated Ca2+ responses were sensitive to NAC and the SOCE inhibitor BTP2, supporting ROS- and SOCE-associated mechanisms. Additional controls showed no significant inhibitor effects under control or CK-only conditions, strengthening the pharmacological interpretation of responses under TMT-containing conditions. Conclusions: TMT-induced Ca2+ dysregulation differed markedly by cell type. CK restored disrupted Ca2+ homeostasis in association with distinct pharmacological signaling profiles in neuronal and astrocytic cells. These findings suggest that CK may function as a cell type-specific Ca2+ homeostatic regulator under neurotoxic stress conditions and highlight the importance of differential Ca2+ regulation in neurodegenerative disease models. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)
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15 pages, 8531 KB  
Article
Simufilam in Alzheimer’s Disease: Assessment of Efficacy of a Controversial Drug in Human Neuronal Cell Culture
by Ankita Srivastava, Heather A. Renna, Tahmina Hossain, Thomas Palaia, Aaron Pinkhasov, Irving H. Gomolin, Joshua De Leon, Thomas Wisniewski and Allison B. Reiss
Pharmaceuticals 2026, 19(2), 281; https://doi.org/10.3390/ph19020281 - 7 Feb 2026
Cited by 1 | Viewed by 2319
Abstract
Background/Objectives: Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is [...] Read more.
Background/Objectives: Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is a small-molecule oral drug that targets filamin A, a scaffolding protein in brain cells. Phase III clinical trials of simufilam failed to show any significant cognitive or functional improvements in AD patients. The purpose of this study is to identify and explain the molecular mechanisms that may have contributed to this drug’s lack of clinical success. Methods: Our study investigates the effects of simufilam on amyloid processing, neuronal health, and mitochondrial functioning in the SH-SY5Y human neuronal cell model. SH-SY5Y cells were differentiated into neurons using 10 µM retinoic acid. Undifferentiated and differentiated SH-SY5Y were exposed to simufilam (5 µM, 50 µM; 24 hr). Results: Simufilam did not affect the expression of genes involved in amyloid processing. Amyloid precursor protein (APP), β-secretase, and α-secretase mRNA levels in simufilam-treated SH-SY5Y cells were all unchanged compared to untreated cells. However, amyloidogenic β-secretase protein was significantly increased (fold change 1.17) at 50 µM of simufilam only in differentiated SH-SY5Y cells without affecting APP or α-secretase protein expression. Simufilam at the 50 µM concentration reduced brain-derived neurotrophic factor protein levels (fold change 0.7) only in differentiated SH-SY5Y. Further, simufilam did not improve mitochondrial genes or structure. Conclusions: Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)
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Review

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24 pages, 3402 KB  
Review
Rhizomes as Multi-Target Pharmacological Platforms Against Tauopathy: Neuro-Metabolic Crosstalk, Drug-Likeness, and Translational Challenges
by Andreas Wilson Setiawan, Jinwon Choi, Sohyun Park, Min Choi, Raymond Rubianto Tjandrawinata, Edwin Hadinata, Moon Nyeo Park, Taruna Ikrar, Fahrul Nurkolis and Bonglee Kim
Pharmaceuticals 2026, 19(5), 792; https://doi.org/10.3390/ph19050792 - 19 May 2026
Viewed by 817
Abstract
Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one [...] Read more.
Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)
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25 pages, 2525 KB  
Review
Targeting Pain and Depression in Alzheimer’s Disease: Translational Insights and Emerging Treatments
by Ivona Costachescu, Gabriela-Dumitrita Stanciu, Raluca Maria Gogu and Bogdan-Ionel Tamba
Pharmaceuticals 2026, 19(4), 626; https://doi.org/10.3390/ph19040626 - 15 Apr 2026
Cited by 1 | Viewed by 1309
Abstract
Alzheimer’s disease (AD) is primarily recognized for progressive cognitive decline driven by beta-amyloid accumulation and tau pathology. However, many individuals with AD also experience chronic pain and depressive symptoms, which significantly impair daily functioning and quality of life and increase caregiver burden. These [...] Read more.
Alzheimer’s disease (AD) is primarily recognized for progressive cognitive decline driven by beta-amyloid accumulation and tau pathology. However, many individuals with AD also experience chronic pain and depressive symptoms, which significantly impair daily functioning and quality of life and increase caregiver burden. These non-cognitive features are frequently underrecognized, despite evidence suggesting they share overlapping biological pathways with neurodegeneration. Emerging data highlight the role of neuroinflammation, oxidative stress, hypothalamic–pituitary–adrenal axis dysregulation, and endocannabinoid system alterations in linking AD pathology to disturbances in pain processing and mood regulation. Persistent microglial activation, cytokine imbalance, redox disruption, and chronic stress signaling may simultaneously promote neuronal vulnerability while shaping affective and nociceptive responses. This review synthesizes current preclinical and clinical evidence on the interplay between pain, depression, and AD, emphasizing their shared pathophysiological mechanisms and clinical relevance. Recognizing these symptoms as integral components of disease progression, rather than isolated comorbidities, can inform the development of integrated, multidimensional therapeutic strategies in AD care. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)
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17 pages, 2575 KB  
Review
Drug-Induced Amyloid-Related Imaging Abnormalities: A Neurovascular Perspective on Risk Assessment
by Marialuisa Zedde, Mattia Losa, Andrea Donniaquio, Ilaria Gandoglia, Massimo Del Sette, Luca Roccatagliata, Fabrizio Piazza, Matteo Pardini and Rosario Pascarella
Pharmaceuticals 2026, 19(4), 579; https://doi.org/10.3390/ph19040579 - 3 Apr 2026
Cited by 1 | Viewed by 2051
Abstract
Background: Anti-amyloid therapies (AAT) are reshaping the therapeutic landscape of Alzheimer’s disease (AD), yet their implementation remains constrained by the risk of amyloid-related imaging abnormalities (ARIA). Although the ARIA phenomenon is well recognized, most available evidence stems from clinical trial safety reports framed [...] Read more.
Background: Anti-amyloid therapies (AAT) are reshaping the therapeutic landscape of Alzheimer’s disease (AD), yet their implementation remains constrained by the risk of amyloid-related imaging abnormalities (ARIA). Although the ARIA phenomenon is well recognized, most available evidence stems from clinical trial safety reports framed predominantly from a dementia-oriented perspective, with relatively limited integration of vascular neurology principles. Methods: In this narrative review, we examine drug-induced ARIA through a neurovascular lens, highlighting how cerebrovascular comorbidity, particularly cerebral amyloid angiopathy (CAA), influences the risk and severity of ARIA. Results: We critically evaluated how CAA comorbidity has been assessed in randomized controlled trials, focusing on exclusion criteria, imaging thresholds, and the resulting implications for external validity. Finally, we evaluated current approaches to ARIA risk stratification and proposed a more integrative framework that combines vascular imaging markers, APOE ε4 genotype, and key clinical comorbidities. Conclusions: A more tailored patient selection and monitoring strategies may ultimately improve real-world outcomes and optimize resources in the era of AAT. Full article
(This article belongs to the Special Issue Pharmacotherapy for Alzheimer’s Disease, 2nd Edition)
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