Journal of Alzheimer's Disease - Volume 101, issue s1

Authors: Moreira, Paula I. | Avila, Jesus | Galimberti, Daniela | Pappolla, Miguel A. | Plascencia-Villa, Germán | Sorensen, Aaron A. | Zhu, Xiongwei | Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-249016

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S1-S2, 2024

Authors: Noorda, Keith | Noorda, Kevin | Sabbagh, Marwan N. | Bertelson, John | Singer, Jonathan | Decourt, Boris

Article Type: Review Article

Abstract: Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as “probable AD”, and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD. Objective: This review aims to evaluate passive immunotherapies deemed to have promise for further development and use …in the treatment of AD. Methods: Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval. Results: This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies. Conclusions: We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology. Show more

Keywords: Alzheimer’s disease, amyloid plaques, clinical trials, FDA approval, passive immunotherapy

DOI: 10.3233/JAD-240189

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S3-S22, 2024

Authors: Vashisth, Kshitij | Sharma, Shivani | Ghosh, Shampa | Babu, M. Arockia | Ghosh, Soumya | Iqbal, Danish | Kamal, Mehnaz | Almutary, Abdulmajeed G. | Jha, Saurabh Kumar | Ojha, Shreesh | Bhaskar, Rakesh | Jha, Niraj Kumar | Sinha, Jitendra Kumar

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological …cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, immunotherapy, personalized medicine, sleep-immune interactions

DOI: 10.3233/JAD-230603

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S23-S39, 2024

Authors: Watkins, Elyse A. | Vassar, Robert

Article Type: Review Article

Abstract: The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer’s disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although …effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer’s disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, beta-secretase, clinical trial

DOI: 10.3233/JAD-231258

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S41-S52, 2024

Authors: Coimbra, Judite R.M. | Resende, Rosa | Custódio, José B.A. | Salvador, Jorge A.R. | Santos, Armanda E.

Article Type: Review Article

Abstract: Disease-modifying therapies (DMT) for Alzheimer’s disease (AD) are highly longed-for. In this quest, anti-amyloid therapies take center stage supported by genetic facts that highlight an imbalance between production and clearance of amyloid-β peptide (Aβ) in AD patients. Indeed, evidence from basic research, human genetic and biomarker studies, suggests the accumulation of Aβ as a driver of AD pathogenesis and progression. The aspartic protease β-site AβPP cleaving enzyme (BACE1) is the initiator for Aβ production. Underpinning a critical role for BACE1 in AD pathophysiology are the elevated BACE1 concentration and activity observed in the brain and body fluids of AD patients. …Therefore, BACE1 is a prime drug target for reducing Aβ levels in early AD. Small-molecule BACE1 inhibitors have been extensively developed for the last 20 years. However, clinical trials with these molecules have been discontinued for futility or safety reasons. Most of the observed adverse side effects were due to other aspartic proteases cross-inhibition, including the homologue BACE2, and to mechanism-based toxicity since BACE1 has substrates with important roles for synaptic plasticity and synaptic homeostasis besides amyloid-β protein precursor (AβPP). Despite these setbacks, BACE1 persists as a well-validated therapeutic target for which a specific inhibitor with high substrate selectivity may yet to be found. In this review we provide an overview of the evolution in BACE1 inhibitors design pinpointing the molecules that reached advanced phases of clinical trials and the liabilities that precluded adequate trial effects. Finally, we ponder on the challenges that anti-amyloid therapies must overcome to achieve clinical success. Show more

Keywords: Alzheimer’s disease, amyloid-β , BACE1, BACE1 inhibitors, clinical trials, disease-modifying therapies, drug discovery

DOI: 10.3233/JAD-240146

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S53-S78, 2024

Authors: Feldman, Howard H. | Messer, Karen | Qiu, Yuqi | Sabbagh, Marwan | Galasko, Douglas | Turner, R. Scott | Lopez, Oscar | Smith, Amanda | Durant, January | Lupo, Jody-Lynn | Revta, Carolyn | Balasubramanian, Archana | Kuehn-Wache, Kerstin | Wassmann, Tanja | Schell-Mader, Sylvia | Jacobs, Diane M. | Salmon, David P. | Léger, Gabriel | DeMarco, Mari L. | Weber, Frank

Article Type: Research Article

Abstract: Background: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimer’s disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. Objective: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND …(NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ. Methods: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. Conclusions: Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD. Show more

Keywords: Alzheimer’s disease, amyloid β-peptides, CCL2, cerebrospinal fluid, glutaminyl cyclase, mild cognitive impairment, N3pE-Aβ , pGlu-Aβ , QPCT, QPCTL

DOI: 10.3233/JAD-231126

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S79-S93, 2024

Authors: Meijer, Laurent | Chrétien, Emilie | Ravel, Denis

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, DYRK1A is overexpressed due to the presence of the DYRK1A gene on chromosome 21. In AD, calcium-activated calpains cleave full-length DYRK1A (FL-DYRK1A) into a more stable and more active, low molecular weight, kinase (LMW-DYRK1A). Genetic and pharmacological experiments carried out with animal models of AD and DS strongly support the idea that pharmacological inhibitors of DYRK1A might be able to correct …memory/learning disorders in people with AD and DS. Starting from a marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, and extensively characterized a small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies in rats and minipigs have been completed and formulation of Leucettinib-21 has been optimized as immediate-release tablets. Leucettinib-21 is now undergoing a phase 1 clinical trial (120 participants, including 12 adults with DS and 12 patients with AD). The therapeutic potential of DYRK1A inhibitors in AD and DS is presented. Show more

Keywords: Alzheimer’s disease, cognitive disorders, Down syndrome, DYRK1A, learning, Leucettinib-21, Leucettinibs, protein kinase

DOI: 10.3233/JAD-240078

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S95-S113, 2024

Authors: Thitilertdecha, Premrutai | Brimson, James Michael

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-β (Aβ deposition is thought to be a key target for treating AD. However, Aβ antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ -2R)/TMEM97 is a binding site for Aβ oligomers. Therefore, targeting the receptor may be beneficial in displacing Aβ oligomers from the brain. CT1812 is a σ -2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective: …The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aβ in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions: CT1812 safely works to displace Aβ however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing. Show more

Keywords: Alzheimer’s disease, amyloid oligomer displacement, clinical data, dementia, Elayta, Sigma receptors, Sigma-2 receptor, Sigma-2 receptor antagonist, TMEM97

DOI: 10.3233/JAD-230994

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S115-S128, 2024

Authors: Sigurdsson, Einar M.

Article Type: Review Article

Abstract:  The tau protein undergoes pathological changes in Alzheimer’s disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of …some antibodies targeting amyloid-β in Alzheimer’s disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer’s disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell. Show more

Keywords: Alzheimer’s disease, antibody, clinical trials, immunotherapy, tau protein, tauopathies, vaccine

DOI: 10.3233/JAD-231238

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S129-S140, 2024

Authors: Du, Bin | Chen, Kang | Wang, Weiwei | Lei, Peng

Article Type: Review Article

Abstract: One pathological feature of Alzheimer’s disease (AD) is the dysregulated metal ions, e.g., zinc, copper, and iron in the affected brain regions. The dysregulation of metal homeostasis may cause neurotoxicity and directly addressing these dysregulated metals through metal chelation or mitigating the downstream neurotoxicity stands as a pivotal strategy for AD therapy. This review aims to provide an up-to-date comprehensive overview of the application of metal chelators and drugs targeting metal-related neurotoxicity, such as antioxidants (ferroptotic inhibitors), in the context of AD treatment. It encompasses an exploration of their pharmacological effects, clinical research progress, and potential underlying mechanisms.

Keywords: Alzheimer’s disease, copper, ferroptosis, iron, metal chelators, zinc

DOI: 10.3233/JAD-240140

Citation: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S141-S154, 2024