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Tailoring MAPK Pathways: New Therapeutics Avenues for Managing Alzheimer’s Diseases

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19 December 2023

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20 December 2023

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Abstract
Neurodegenerative diseases like Alzheimer's diseases are irreversible, progressive, and refractory in nature and managed very poorly. AD is manifested with the aggregation of unfolded proteins, synaptic pathology and dementia and poses challenges to the health care system globally. Only very few treatments with minimal effect are available to the patients and their caregivers. Despite numerous clinical trials which were launched for AD, unfortunately, most of them failed in satisfying the pharmacological criteria. At cellular levels, many signaling pathways have been proposed for the sterile / refractory behavior of degenerating neurons. Among those, Mitogen activated protein kinases (MAPKs) are the critical cellular networks which are involved in the development of Alzheimer’s disease. Several studies have demonstrated a favorable impact of MAPK inhibition on inflammatory programming, synaptic plasticity, and memory problems in mouse models of AD. In view of this, various clinical trials were launched with several MAPK inhibitors (with good safety profile and less side-effects) have yielded positive results in AD patients suggesting that MAPK targeting may be effective for reducing the pathogenesis of AD, but due to selectivity, dosing and patient stratification, this aspect still need development. In view of selectivity and off-target effects, only a few MAPK inhibitors have been employed in clinical trials against AD indicating a scope of development in this area. Therefore, this study focuses on MAPK based interventions as an upcoming and innovative approach for alleviating AD with special emphasis on clinical studies.
Keywords: 
Subject: Medicine and Pharmacology  -   Neuroscience and Neurology

Highlights

  • MAPK are decisive for neuro-immunological interaction and synapses
  • Imbalance of MAPK pathways disrupts neuronal immune-homeostasis
  • Readjusting MAPKinome improves immuno-epigenetic response
  • MAPK based clinical trials offer therapeutic advantage for AD

Introduction

In recent decades, kinases have emerged as a prominent focus of research in pharmacology due to their central roles in regulating a diverse range of cellular processes 1. Substantial efforts have been dedicated to developing molecules that specifically target the human kinome, reflecting their significance as potential drug targets 2. Currently, there are over 250 kinase inhibitors in clinical trials, with 48 already approved by the U.S. Food and Drug Administration (FDA), primarily for treating malignancies. These inhibitors have had a significant impact on cancer therapy, particularly in cases driven by a single oncogenic kinase, such as chronic myeloid leukemia and gastrointestinal stromal tumors3. In contrast to oncology, MAPK / kinome based therapeutic approaches are still under early stage of development in neurodegenerative disorders like Alzheimer’s disease (AD) and the precise contribution of dysregulated human kinome in the context of neurodegeneration remains elusive. In particular, understanding the neuronal functions of various kinases is a critical area that requires further exploration. The roles of many kinases in neuronal tissues are yet to be fully characterized therefore filling this lacuna in managing / modifying neuro-degenerative diseases is paramount. Understanding the precise role of MAPK family members across different brain regions during progression of neurodegenerative diseases conditions will shed light on potential therapeutic strategies. Mammalian cells possess four primary MAPK pathways that trigger the activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase 5 (ERK5), also known as Big MAP kinase-1 (BMK1). The mammalian pathways exhibit increased complexity due to the presence of multiple gene products, such as ERK1 and ERK2, JNK1, JNK2, and JNK3, as well as p38α, p38β, p38γ, and p38δ. Due to their critical roles in human diseases, mitogen-activated protein kinases (MAPK) have been targeted / explored for modifying pathology / pathogenesis of various disease models 4.
During the last few years, Ras/Raf/MAPKs pathway has emerged as potential / plausible drug targets in many neurodegenerative diseases (NDDs) such as Parkinson’s, Alzheimer’s, stroke, aging, and neurodegeneration5-8 etc. Due to this, the current study highlights the importance of targetable MAPK in NDDs, with a particular emphasis on clinical trial / studies.

Alzheimer’s Disease: Progressive Neurodegenerative Ailment

Alzheimer’s disease is a terminal dementing neurodegenerative disease of elderly population and is clinically recognized as a slow decline in memory and cognitive function as well as other abnormalities. The majority of AD patients have the sporadic form of the disease. The mortality rate among AD patients rose by 71% from 2000 till 2013 in the United States, where it is ranked as the sixth greatest cause of death. Less than 5% of AD patients have a familial history of disease, which is associated with the mutations in APP, PS1, and PS2 genes 9.
The brain in AD patients is characterized by the extracellular accumulation of senile plaques, intracellular neuro fibrillary tangles. Neuro-pathological lesions of AD are vascular in nature with fibrotic lesions showing oxidative stress and tau pathology. AD is manifested with the aggregation of Amyloid beta, synaptic loss, microglial cell reactivity, excitotoxicity, loss of mitochondrial membrane potential and intracranial accumulation of glycation end products10,11. Very little is known on the key factors / mechanism which trigger the pathogenesis of AD in the healthy brain.

Beta Amyloid Specific Interventions for AD

Perturbation in glia-neuron axis and breakage of homeostasis is believed to trigger the pathogenesis of AD which is manifested by the infiltration of effector immune cells and their interaction with damaged neurons subsequently leads to neuronal fibrosis in the cerebral region 12. This is orchestrated by the release of beta amyloid from damaged neurons which trigger pathogenic inflammation in brain, which is accompanied with the accumulation of βA peptide, which subsequently leads to synaptic loss and augment neuronal cell death which is overriding pathological feature of AD 13.
Inflammation is mainly mediated by microglial cells which are resident immune cells in the central nervous system (CNS). In AD, microglia has been known to be chronically activated, resulting in impairment of Aβ clearance, overexpression of pro-inflammatory signals, and consequently, neurotoxicity. Therefore, the regulation of microglial activation may be an important therapeutic strategy of AD by lowering excessive pro-inflammatory immune chemotaxis and enhancing neuroprotective function, leading to the modulation of neuro-inflammation 13,14.
Infact, for the last couple of decades, several clinical trials involving AD patients / subjects have targeted beta-amyloid (Aβ) for limiting the progression and pathology of AD as shown in Table 1.
According to recent studies, either development of various inhibitors of Amyloid beta and tau protein synthesis or mimetics for their degradation seems to be the most pertinent strategies for modifying AD. So far none of tau-related agents have been approved by regulatory authorities for the treatment of AD 15. Till date, 187 trials have been launched which assessed 141 drugs targeting various signaling components involved in the progression of AD15 as shown in Figure 1.

MAPK Based Intervention of Alzheimer Diseases

Out of several signaling pathways which are involved in the pathogenesis of AD, MAPK pathways are the most intricate pathways which promote stress related adaptation and orchestrate desmoplastic reactions leading to the pathogenic inflammation, neuronal death7,16. MAPK is a non-canonical pathway that gets activated by aberrant neuronal-microglia interaction 17(also known as stromal reactions) as shown in Figure 2a.
MAPK constitutes several proteins and among them p38 is one of the three MAPKs family members which are primarily activated by pro-inflammatory cytokines (Th1/ Th17 effectors) and environmental stresses caused by dying neurons. p38 MAPKs have four isoforms which are further categorized in p38α, β, γ and δ 18. Among these, p38α andβ MAPKs are highly expressed in the adult mouse brain and involved in AD pathogenesis19. p38α regulates inflammatory programming of the brain via tempering microglia20 and astrocytes21. MAPK is a complex and multifaceted pathway which also connects different neurological disorders as shown in Figure 2a like Alzheimer’s and ischemic stroke8,22,23. Research is also going in this area whereby inhibiting the MAPK pathway using MAPK inhibitors both neurological diseases can be ameliorated as shown in Figure 3.
During the progression of AD, p38 expression is enhanced in damaged neurons, contributing to amyloid-beta toxicity, inflammation, and tau phenomena on synaptic clefts as shown in Figure 2b. Study with transgenic animals (APP/PS1, aged rats, Tau mice) revealed that deleting the p38α selective kinase reverses the AD symptom which were induced by amyloid-beta, inflammation, or tau. The study also links neuronal p38α signalling to the impairment of memory and synaptic plasticity seen in 5XFAD animals. This is because it regulates the build-up of amyloid-β in the brain as well as how this accumulation is relayed to trigger an inflammatory response, which results in cognitive deficiencies24. A highly selective p38α inhibitor was administered as part of a clinical investigation on sixteen patients diagnosed with early AD. The findings suggest that selective p38α inhibition may enhance episodic memory and perhaps influence the development of β-amyloid in patients with early AD. These first clinical results lend support to carrying out a longer-term, placebo-controlled investigation, especially to validate the effects on episodic memory function25. A compelling study has indicated that two neuron specific micro RNA, miR-124/128 directed loss of p38α in primary mouse cerebral granule cell culture, leads to the down regulation of signal transduction of p38α MAPK pathway and declining neuro-pathogenesis26. Mechanistically, p38α disrupts proteostasis in neurons by promoting unfolded protein responses (UPR) impair autophagy-mediated protein degradation and endolysosome functions27 which are essential for synaptic function28. Clinical trials with several MAPK specific inhibitors have (Table 2 and Table 3) have shown their impact in ameliorating AD pathology.

Redefining New Strategies for Managing AD

Several drugs like gantenerumab, solanezumab, and aducanumab have been explored in AD patients for either inhibiting Aβ production (e.g., β- and γ-secretase inhibitors), enhancing Aβ clearance, or neutralizing it with humanized monoclonal antibodies however these interventions could only modify the AD symptoms only minimally and transiently with less stable outcomes of these interventions have not been encouraging as shown in Table 1. To circumvent challenges in designing prevention trials for late-onset sporadic AD, the innovative DIAN-TU (Dominantly Inherited Alzheimer Network Trials Unit) was initiated. DIAN-TU, a phase 2/3 trial, focused on primary prevention for the autosomal dominant form of AD, which has a known link to Aβ dysfunction and early cognitive decline29. Regrettably, a preliminary analysis of the trial revealed that both investigational anti-amyloid drugs, Roche’s gantenerumab and Lilly’s solanezumab, did not meet the primary endpoint criteria (DIAN-Multivariate Cognitive Endpoint)30. In October 2019, phase 3 study was conducted using aducanumab’s which also could not offer clinical advantage and could not modify the diseases severity31. The negative outcomes with the above biological agents lead to the beginning of newer approaches targeting intracellular signaling components (e.g. MAPK) in AD and related neurodegenerative dementias. Due to stringent involvement of MAPK in AD pathogenesis, p38 specific inhibitors were employed in ameliorating the AD pathology. Some of MAPK inhibitors have been used in interventional studies while some of them are not used in clinical trials yet but have been tested both in vivo / vitro.

p38 inhibitors

 

Neflamapimod

Vertex Pharmaceuticals originally developed neflamapimod for rheumatoid arthritis, progressing to phase 2a. Later EIP Pharma acquired rights in 2014, using it against CNS disorders. Neflamapimod (formerly known as VX-745) is a potent ATP competitive inhibitor of p38α kinase, showing strong inhibition of p38α in vitro with an IC50 of 9nM in bringing down beta amyloid / tau-induced toxicity and neuro-inflammation. This is currently under phase 2b trial for abolishing synaptic dysfunction. Neflamapimod targets neuronal mechanisms, addressing synaptic dysfunction, a key factor in early Alzheimer’s disease. Phase 2a study results showed memory improvement prompting a planned 2b study32. Another compelling study showed that selective inhibition of p38α with neflamapimod improved episodic memory and inhibited the turnover of amyloid turnover viz –a viz autophagy in repaired neuronal cells33. A 6-month placebo-controlled study has recently been initiated to confirm these preliminary clinical findings which targeted Neflamapimod targets like ABL1, ABL2, p38β, PDGFRβ, and SRC34.

SB203580

SB203580 is a traditional p38α/β MAPK inhibitor and had shown therapeutic effects in mouse model of AD as well as the LPS-induced depression model35. SB203580 inhibits p38 catalytic activity by binding to the ATP binding pocket36. Administration of SB203580 in animals with AD significantly reversed the altered phosphorylation levels of p38 in the habenula, neuro-inflammation induced depressive-like behaviors, which were accompanied by increased levels of TNF-α and p-p38 in the habenula37. The p38 inhibitor SB203580 reduced the level of TNF-α and up-regulated the levels IL-10 in the habenula37

MW150-

MW-150, also showed therapeutic effects in the AD mouse model. Although, intervention of AD mice with MW150 attenuated the increased levels of IL-1β and TNFα, yet it increased the IBA1+ microglia within amyloid plaques, without significantly affecting overall microglia or plaque volume38. MW150 is capable of reducing neuro-inflammatory responses while dispensing physiological functions of microglia. These results potentially indicated the therapeutic impact of inhibiting microglia specific p38MAPK in modulating disease biology of AD38. Additional research indicates that MW150 can selectively block the stress-activated p38α MAPK, thereby attenuating the entorhinal cortex dysfunctions linked to neuro-inflammation during the early stages of Alzheimer’s disease progression39.

NJK14047-

NJK14047 as a selective p38α/β MAPK inhibitor reduces the level of phospho-p38 MAPKs in the brain and attenuates spatial memory loss in 9-month-old 5XFAD mice40. In a study, with NJK14047; a novel and selective p38 inhibitor, it was shown for the first time that it suppressed activation and reduced the secretion of pro-inflammatory cytokines in LPS stimulated microglia such as TNF-α, IL-1β and IL-6 through the inhibition of p38 MAPK activation in BV2 microglia in mouse model41. It reduced the expression of iNOS and COX-2 proteins which are the marker of M1 effector microglia which are involved in pathogenic neuro- inflammation41.

Exantide

This molecule alleviated mitochondrial dysfunction and cognitive impairment in the 5XFAD mouse model of Alzheimer’s disease. In conclusion, it was shown that exenatide treatment improved cognitive impairment, reduced Aβ1-42 deposition, and alleviated synaptic degradation in 5XFAD mice suggesting that exenatide may be a promising new therapeutic candidate for AD42.

Minocycline

Minocycline is a semisynthetic tetracycline derivative that inhibits the p38 mitogen-activated protein kinase (MAPK) pathway. One animal study shows that intrathecal administration with minocycline not only attenuates morphine anti-nociceptive tolerance, but also activation of spinal microglia / astrocyte induced by chronic morphine treatment43.

Limitations/Bottlenecks

In spite of available MAPK inhibitors which we have discussed above, only a few have been studied in clinical trials (Table 3) with heterogeneous outcome as disease modifying potential. The ability of these inhibitors to cross impermeable BBB is one of the main constraints for many inhibitors which are currently in clinical trials. This is not limited to protein kinase inhibitor drugs, however, as it is estimated that >95% of approved drugs lack sufficient brain tissue exposure. CNS exposure limitation is most often linked to the molecular properties of the small molecule drugs and this barrier can be addressed through medicinal chemistry refinement44. Therefore designing / screening BBB permeable inhibitors is paramount requirement for enhancing the efficacy of MAPK for AD. The p38 MAPK pathway contributes to neuro-inflammation mediated by microglia and astrocytes. p38α appears to be the main isoform involved in the inflammatory response. p38MAPK mediated pro-inflammatory programming of CNS contribute to the development of AD. p38α and p38β, expressed in the brain, are often activated in animal models of neurodegeneration, leading to altered physiological properties, activation of responsive genes and neurotoxicity.

Conclusions

Taken together, these observations are consistent with the hypothesis that specific p38 MAPK isoforms have a role in the pathogenesis of neurodegenerative diseases, potentially making them attractive therapeutic targets. Although proof of principle experiments in preclinical models have shown that inhibitors of p38MAPK can have neuroprotective effects, an evaluation of inhibitors that are able to bypass the blood–brain barrier is needed to evaluate this in human clinical trials. Combinatorial therapy must be taken into consideration where a cocktail of P38 inhibitors should be formulated to see the synergistic effects on neuro-inflammation. More target engagement biomarkers, better clinical measures, and new approaches to assessment, such as computerized tests and digital biomarkers, may improve the ability to characterize drug-placebo differences and advance novel therapies for AD.

Abbreviation

MAPK Mitogen Activated Protein Kinase
ERK Extracellular Signal-Regulated Kinase
TNFα Tumor Necrosis Factor Alpha
TNFR Tumor Necrosis Factor Receptor
IL1 Interleukin-1
IL1R Interleukin-1 Receptor
TGFβ Transforming Growth Factor-Beta
TGFβR Transforming Growth Factor-Beta Receptor
TRADD TNFR1-Associated Death Domain Protein
MYD88 Myeloid Differentiation Factor 88
DAXX Death Domain Associated Protein
TRAF TNF Receptor-Associated Factor
ASK1 Apoptosis Signal-Regulating Kinase 1
IRAK Interleukin-1 Receptor-Associated Kinase
MKK Mitogen Activated Protein Kinase Kinase
TAB Transforming Growth Factor Beta-Activated Kinase 1-Binding Protein
CDC25B Cell Division Cycle 25B
ATF Activating Transcription Factor
ELK ETS Like-1 Protein
SAPLA Regulatory Subunit of Serine/Threonine-Protein Phosphotase 6
GADD Growth Arrest and DNA Damage-Inducible Protein
MAX MYC Associated Factor X
MEF2C Myocyte-Specific Enhancer Factor 2C
TLR Toll-Like Receptors
RAGE Receptor for Advanced Glycation Endproducts
NF-KB Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells
XIAP X-Linked inhibitor of Apoptosis Protein
ASC Apoptosis-Associated Speck-Like Protein
NLRP1/3 NLR Family Pyrin Domain Containing 1/3
5XFAD Familiar Alzheimer Disease Mice Bear 5 AD-Linked Mutation

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Figure 1. Evolution of Alzheimer;s therapeutics: Shown here is the comprehensive journey of MAPK inhibitors which have been explored in various single / multicentre clinical trials for developing AD therapeutics.
Figure 1. Evolution of Alzheimer;s therapeutics: Shown here is the comprehensive journey of MAPK inhibitors which have been explored in various single / multicentre clinical trials for developing AD therapeutics.
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Figure 2. Impact of p38 mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of Alzheimer’s disease (AD) (a) This diagram shows the interaction between microglia and neuron in Alzheimer’s. The build up of amyloid beta plaques activates microglia leading to chronic inflammation and activation of p38MAPK pathway causing neuronal apoptosis. The CD36 along with TLR2/4/6, and RAGE binds to amyloid beta and trigger the activation of p38 MAPK signalling pathway in microglia leading to the production of pro-inflammatory cytokines, such as TNFα, TGFβ binding to their receptors on neurons. TRADD / TRAF are proteins involved in the signalling pathway of TNFα leading to activation of ASK1. GADD153 and Sapla are proteins induced by p38 MAPK. GADD153 has been shown to be involved in the apoptosis of neurons in AD while Sapla is involved in the regulation of gene expression in neurons. ATF-2 is a transcription factor that gets activated by p38 MAPK. It has been shown to be involved in p53 signalling pathway. Cdc25B is a phosphatase that is activated by p38 MAPK. It has been shown to be involved in the regulation of cell cycle progression. However, in Alzheimer’s disease, CDC25B activity increases the abnormal expression of Cdc2/cyclin B, resulting in various downstream indicators of mitotic events and eventually leading to neuro-degeneration. A substantial increase in p53 activity and its level has been documented in AD and intracellular Aβ42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus, demonstrating an alternative pathogenesis in AD45-47. b) the figure showing the central role of p38MAPK leading to the activation and inhibition of several processes in AD.
Figure 2. Impact of p38 mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of Alzheimer’s disease (AD) (a) This diagram shows the interaction between microglia and neuron in Alzheimer’s. The build up of amyloid beta plaques activates microglia leading to chronic inflammation and activation of p38MAPK pathway causing neuronal apoptosis. The CD36 along with TLR2/4/6, and RAGE binds to amyloid beta and trigger the activation of p38 MAPK signalling pathway in microglia leading to the production of pro-inflammatory cytokines, such as TNFα, TGFβ binding to their receptors on neurons. TRADD / TRAF are proteins involved in the signalling pathway of TNFα leading to activation of ASK1. GADD153 and Sapla are proteins induced by p38 MAPK. GADD153 has been shown to be involved in the apoptosis of neurons in AD while Sapla is involved in the regulation of gene expression in neurons. ATF-2 is a transcription factor that gets activated by p38 MAPK. It has been shown to be involved in p53 signalling pathway. Cdc25B is a phosphatase that is activated by p38 MAPK. It has been shown to be involved in the regulation of cell cycle progression. However, in Alzheimer’s disease, CDC25B activity increases the abnormal expression of Cdc2/cyclin B, resulting in various downstream indicators of mitotic events and eventually leading to neuro-degeneration. A substantial increase in p53 activity and its level has been documented in AD and intracellular Aβ42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus, demonstrating an alternative pathogenesis in AD45-47. b) the figure showing the central role of p38MAPK leading to the activation and inhibition of several processes in AD.
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Figure 3. p38MAPK inhibitions in amyloid beta induced neurotoxic environment: The amyloid beta is produced primarily in the intracellular compartments of neurons by the proteolytic cleavage of Amyloid Precursor Proteins which is then secreted outside to form the sticky plaques that causes the death of brain cells. The amyloid beta toxicity initiates the p38MAPK pathway that further initiates the transcription of pro-inflammatory cytokines, pro-apoptotic proteins and inflammasome proteins as shown. However, the p38MAPK inhibitors that are in the clinical trials have shown a significant impact in AD patients and have demonstrated themselves very useful in ameliorating the neurotoxic environment by reducing the chronic inflammation and brain cell death.
Figure 3. p38MAPK inhibitions in amyloid beta induced neurotoxic environment: The amyloid beta is produced primarily in the intracellular compartments of neurons by the proteolytic cleavage of Amyloid Precursor Proteins which is then secreted outside to form the sticky plaques that causes the death of brain cells. The amyloid beta toxicity initiates the p38MAPK pathway that further initiates the transcription of pro-inflammatory cytokines, pro-apoptotic proteins and inflammasome proteins as shown. However, the p38MAPK inhibitors that are in the clinical trials have shown a significant impact in AD patients and have demonstrated themselves very useful in ameliorating the neurotoxic environment by reducing the chronic inflammation and brain cell death.
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Table 1. Humanized monoclonal antibodies in the current Alzheimer’s disease pipeline. (Data is downloaded from https://clinicaltrials.gov/).
Table 1. Humanized monoclonal antibodies in the current Alzheimer’s disease pipeline. (Data is downloaded from https://clinicaltrials.gov/).
NCT Agent Study title Status/result Target Phase study summary Comments
NCT00890890 Avagacestat A Multicenter, Double Blind, Placebo Controlled, Safety and Tolerability Study of BMS-708163 in Patients With Prodromal Alzheimer’s Disease Terminated/ No Gamma secretase inhibitor II The purpose of this study is to determine the safety and tolerability of BMS-708163 in patients with Prodromal Alzheimer’s disease over a treatment period of a minimum of 104- weeks. In addition patients will be seen for safety visits at 4 and 12 weeks post treatment. Safety and tolerability of BMS-708163 in patients with Prodromal Alzheimer’s disease as measured by adverse events, vital signs, laboratory assessments, electrocardiograms (ECGs) and Safety Head Magnetic resonance imaging (MRI) findings,
Every 12 weeks up to week 220|
NCT00810147 BMS-708163 A Phase II, Multicenter, Double Blind, Placebo-Controlled Safety, Tolerability Study of BMS-708163 in Patients With Mild to Moderate Alzheimer’s Disease Completed/No 2 The purpose of this study is to determine the safety and tolerability of BMS-708163 in patients with mild to moderate Alzheimer’s disease over a treatment period of 12-weeks and the course of any potential effects during a
12-week wash-out period		 Adverse Events
NCT01039194 BMS-708163 Drug-Drug Interaction to Study the Effect of BMS-708163 on Pharmacokinetics (PK) of
Galantamine Extended Release (ER)		 Completed/No 1 The purpose of the study is to find out if the plasma concentration of galantamine extended release is changed when BMS-708163 is
administered at the same time.		 Safety and tolerability
NCT00726726 BMS-708163 +
Cooperstown Cocktail		 Drug Interaction Study With a Potential Alzheimer’s Disease Compound Completed/No 1 The purpose of this study is to determine whether BMS-708163 will affect the pharmacokinetics of the commonly prescribed medicines midazolam, warfarin,
caffeine, omeprazole and dextromethorphan		 Adverse events
NCT01042314 BMS-708163 Drug-Drug Interaction Study With Aricept® (Donepezil) Completed/No 1 The purpose of this study is to find out if the plasma concentration of donepezil is changed when BMS-708163 is administered at the same
time		 Safety and tolerability
NCT01079819 BMS-708163 Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of BMS-708163 Completed/No 1 The purpose of the study is to evaluate the pharmacokinetics, safety and tolerability of BMS-708163 administered as single and
multiple doses in Chinese subjects		 Adverse events
NCT01035138 Semagacestat A Study of Semagacestat for Alzheimer’s Patients Completed/ yes Monoclonal antibodies to Aβ or its oligomers or fibrils 3 The primary objective of the original study was to assess the safety of semagacestat in Alzheimer’s disease (AD) patients during 24 months of open-label treatment. Baseline for the efficacy measures is defined as the baseline for feeder studies LFAN (NCT00594568) and LFBC (NCT00762411). For all safety analyses (adverse events), baseline for patients will be week 0 of this study (LFBF). semagacestat did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform
activities of daily living.
Preliminary results from LFAN and LFBC showed Study drug was stopped in all studies. Very few participants from LFBC rolled over into LFBF (N = 9). Due to insufficient sample size, the data for LFBC participants who rolled into LFBF were not analyzed.
NCT00663026 Bapineuzuma b Study Evaluating Bapineuzumab In Alzheimer Disease Subjects Completed/ yes Monoclonal antibodies to Aβ or its oligomers or fibrils 2 The study will evaluate the safety and effectiveness of bapineuzumab for the treatment of mild to moderate Alzheimer disease. Subjects will be in the study for six months and will receive subcutaneous
injections once per week.		 Adverse events and serious adverse events.
NCT00676143 Bapineuzuma b Study Evaluating the Safety and Efficacy of Bapineuzumab in Alzheimer Disease Patients Terminated / yes Monoclonal antibodies to Aβ or its oligomers or fibrils 3 This is a study to evaluate the efficacy and safety of multiple doses of bapineuzumab in patients with mild to moderate Alzheimer Disease. Patients will receive either bapineuzumab or placebo. Each patient’s participation will last approximately 1.5 years. Alzheimer’s Disease Assessment Scale- Cognitive (ADAS-Cog)/11 Subscale Total Score at Week 78,
NCT00996918 Bapineuzuma b A Long-Term Safety And Tolerability Study Of Bapineuzumab In Alzheimer Disease Patients Terminated / yes Monoclonal antibodies to Aβ or its oligomers or fibrils 3 The purpose of this study is to assess the long- term safety and tolerability of bapineuzumab in subjects with Alzheimer Disease who participated in study 3133K1-3000 (NCT00667810). Over 250 sites will participate in over 26 countries. Subjects will receive bapineuzumab. Each subject’s participation will
last approximately 4 years.		 Adverse events
NCT03639987 Aducanumab A Study of Aducanumab in
Participants With Mild Cognitive		 Terminated/ yes Monoclonal
antibodies to Aβ		 2 The primary objective of the study is to assess
the safety impact of continuing aducanumab		 Number of Participants with Clinically
Impactful Amyloid-related Imaging
NCT02484547 Aducanumab 221AD302 Phase 3 Study of
Aducanumab (BIIB037) in Early		 Terminated/ yes Monoclonal
antibodies to Aβ		 3 The primary objective of the study is to
evaluate the efficacy of monthly doses of		 Change From Baseline in Clinical
Dementia Rating Scale - Sum of Boxes
NCT02477800 Aducanumab 221AD301 Phase 3 Study of
Aducanumab (BIIB037) in Early		 Terminated/ yes Monoclonal
antibodies to Aβ		 3 The primary objective of the study is to
evaluate the efficacy of monthly doses of		 Change From Baseline in Clinical
Dementia Rating Sum of Boxes (CDR-
NCT05108922 Aducanumab A Study of Donanemab (LY3002813)
Compared With Aducanumab in		 Active not
recruiting/ No		 Monoclonal
antibodies to Aβ		 3 The main purpose of this study is to compare
donanemab to aducanumab on amyloid plaque
NCT01677572 Aducanumab Multiple Dose Study of Aducanumab
(BIIB037) (Recombinant, Fully		 TERMINATED/ No Monoclonal
antibodies to Aβ		 1 The primary objective of this study is to
evaluate the safety and tolerability of multiple		 Number of Participants with Adverse
Events, Baseline to week 518
NCT01397539 Aducanumab Single Ascending Dose Study of
BIIB037 in Participants With		 COMPLETED/ No Monoclonal
antibodies to Aβ		 1 The primary objective of the study is to
evaluate the safety and tolerability of a range		 Number of Participants with Adverse
Events as a Measure of Safety and
NCT05310071 Aducanumab A Study to Verify the Clinical Benefit
of Aducanumab in Participants With		 RECRUITING/ No Monoclonal
antibodies to Aβ		 3 The primary objective of this study is to verify
the clinical benefit of monthly doses of		 Change From Baseline in CDR-SB Score
at Week 78, impairment. Positive
NCT02782975 Aducanumab Absolute Bioavailability of a Single,
Fixed Subcutaneous Dose of		 COMPLETED/ No Monoclonal
antibodies to Aβ		 1 The primary objectives of this study are to
evaluate the absolute bioavailability of a single,		 PK parameter of SC dose of
aducanumab: Absolute Bioavailability,
NCT04241068 Aducanumab A Study to Evaluate Safety and Tolerability of Aducanumab in
participants With Alzheimer’s		 ACTIVE_NOT_RECR UITING/ No Monoclonal antibodies to Aβ
or its oligomers		 3 The primary objective is to evaluate the safety and tolerability of aducanumab over 100 weeks
of treatment after a wash-out period imposed		 Number of Participants with Adverse Events (AEs) and Serious Adverse
Events (SAEs): Number of Participants
NCT02434718 Aducanumab Single and Multiple Ascending Dose Study of Aducanumab (BIIB037) in Japanese Participants With Alzheimer’s Disease COMPLETED/ No Monoclonal antibodies to Aβ or its oligomers or fibrils 1 The primary objective of the study is to evaluate the safety and tolerability of single and multiple intravenous (IV) infusions of Aducanumab in Japanese participants with mild to moderate Alzheimer’s Disease (AD). The secondary objectives of this study are as follows: To evaluate the serum pharmacokinetics (PK) of Aducanumab after single and multiple intravenous (IV) infusions of Aducanumab; To evaluate the effect of single and multiple IV infusions of Aducanumab on
immunogenicity.		 Incidence and nature of adverse events (AE) / serious adverse events(SAE), Up to week 42 abnormalities in neurological and physical examinations, Up to week 42|Brain magnetic resonance imaging (MRI) findings to assess amyloid- related imaging abnormalities (ARIA), including incidence of ARIA-E (edema) or ARIA-H (hemosiderosis), Up to week 42
NCT01767311 Lecanemab A Study to Evaluate Safety, Tolerability, and Efficacy of Lecanemab in Subjects With Early Alzheimer’s Disease Active not Monoclonal antibodies to Aβ or its oligomers or fibrils 2 This is a multinational, multicenter, double- blind, placebo-controlled, parallel-group study using a Bayesian design with response adaptive randomization across placebo or 5 active arms of lecanemab to determine clinical efficacy and to explore the dose response of lecanemab using a composite clinical score (ADCOMS). adverse events (AEs) and serious adverse events (SAEs)
Recruiting/No
NCT03887455 Lecanemab A Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer’s Disease Active_not_recruitin g/ No Monoclonal antibodies to Aβ or its oligomers or fibrils 3 This study will be conducted to evaluate the efficacy of lecanemab in participants with early Alzheimer’s disease (EAD) by determining the superiority of lecanemab compared with placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR- SB) at 18 months of treatment in the Core Study. This study will also evaluate the long- term safety and tolerability of lecanemab in participants with EAD in the Extension Phase and whether the long-term effects of lecanemab as measured by the CDR-SB at the end of the Core Study is maintained over time in the Extension Phase. Adverse event that emerges during treatment or within 30 days of the last dose of study drug. Worsens in severity during treatment relative to the pretreatment state, when the adverse event was continuous
NCT04468659 Lecanemab AHEAD 3-45 Study: A Study to Evaluate Efficacy and Safety of Treatment With Lecanemab in Participants With Preclinical Alzheimer’s Disease and Elevated Amyloid and Also in Participants With Early Preclinical Alzheimer’s Disease and Intermediate Amyloid Recruiting/No Monoclonal antibodies to Aβ or its oligomers or fibrils 3 The primary purpose of this study is to determine whether treatment with lecanemab is superior to placebo on change from baseline of the PACC5 at 216 weeks of treatment (A45 Trial) and to determine whether treatment with lecanemab is superior to placebo in reducing brain amyloid accumulation as measured by amyloid (PET) at 216 weeks of
treatment (A3 Trial).		 Preclinical Alzheimer Cognitive Composite 5 (PACC5) Score at Week 216
NCT05738486 Donanemab A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6) RECRUITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils This study will investigate different donanemab dosing regimens and their effect on the frequency and severity of ARIA-E in adults with early symptomatic Alzheimer’s disease (AD) and explore participant characteristics that might predict risk of ARIA. Percentage of Participants with Any Occurence of Amyloid-Related Imaging Abnormality-Edema/Effusion (ARIA-E), 24 Weeks
NCT05108922 Donanemab A Study of Donanemab (LY3002813) Compared With Aducanumab in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-
ALZ 4)		 ACTIVE_NOT_RECR UITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils The main purpose of this study is to compare donanemab to aducanumab on amyloid plaque clearance in participants with early symptomatic Alzheimer’s Disease (AD).
NCT05508789 Donanemab A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5) RECRUITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils The reason for this study is to assess the safety
and efficacy of donanemab in participants with early Alzheimer’s disease. The study duration including screening and follow-up is up to 93 weeks.		 Change from Baseline on the
Integrated Alzheimer’s Disease Rating Scale (iADRS), Change from Baseline on the iADRS in at least one of ’the low medium tau pathology population or
NCT05026866 Donanemab A Donanemab (LY3002813) Prevention Study in Participants With Alzheimer’s Disease (TRAILBLAZER-ALZ 3) RECRUITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils The main purpose of this study is to evaluate the safety and efficacy of donanemab in participants with preclinical Alzheimer’s Disease (AD). Time to clinical progression as measured by Clinical Dementia Rating Global Score (CDR-GS), participant’s stage on the spectrum of AD dementia., Estimated Up to Week 182
NCT04640077 Donanemab A Follow-On Study of Donanemab (LY3002813) With Video Assessments in Participants With Alzheimer’s Disease (TRAILBLAZER- EXT) ACTIVE_NOT_RECR UITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils The main goals of this study are to further determine whether the study drug donanemab is safe and effective in participants with Alzheimer’s disease and to validate video scale assessments. Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog13). A summary of serious and other non- serious adverse events regardless of causality is located in the Reported Adverse Events module., Up to 72 Weeks
NCT04437511 Donanemab A Study of Donanemab (LY3002813) in Participants With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 2) ACTIVE_NOT_RECR UITING/No Monoclonal antibodies to Aβ or its oligomers or fibrils The reason for this study is to see how safe and effective the study drug donanemab is in participants with early Alzheimer’s disease. Change from Baseline on the integrated Alzheimer’s Disease Rating Scale (iADRS), Change from Baseline on the iADRS in participants with early symptomatic AD in at least one of ’the low-medium tau pathology population or the overall population’., Baseline, Up to Week 76
Additional participants will be enrolled to an addendum safety cohort. The participants will be administered open-label donanemab.
NCT01224106 Ganteneruma
b		 A Study of Gantenerumab in
Participants With Prodromal		 Completed/Yes Monoclonal
antibodies to Aβ		 3 This multi-center, randomized, double-blind,
placebo-controlled parallel-group study.		 Adverse Events (AEs) or Serious
Adverse Events (SAEs)
NCT02051608 Ganteneruma b A Study of Gantenerumab in Participants With Mild Alzheimer Disease Completed/Yes Monoclonal antibodies to Aβ or its oligomers or fibrils 3 Part 1 is a multicenter, randomized, double- blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE). Adverse Events (AEs) or Serious Adverse Events (SAEs)
NCT01998841 Crenezumab Completed/Yes 2 Study evaluates the efficacy and safety of Crenezumab versus Placebo in participants who carry the PSEN1 E280A autosomal- dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are thus, in a
preclinical phase of AD.		 Adverse Events (AEs) and Serious Adverse Events (SAEs)
NCT01723826 Crenezumab Completed/Yes 2 study will evaluate the long-term safety and tolerability of crenezumab in participants with mild to moderate Alzheimer’s disease who have participated in and completed the treatment period of the Phase II Study ABE4869g (NCT01343966) or ABE4955g
(NCT01397578). Participants who received placebo in Study ABE4869g (NCT01343966) or ABE4955g (NCT01397578) will receive crenezumab. Anticipated time on study treatment is 144 weeks.		 Adverse Events (AEs)
NCT02760602 Solanezumab A Study of Solanezumab (LY2062430) in Participants With Prodromal Alzheimer’s Disease Terminated/yes 3 The main purpose of this study is to investigate the safety and efficacy of the study drug solanezumab in participants with prodromal
Alzheimer’s disease (AD).		 Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS- Cog14) Score
NCT01900665 Solanezumab Progress of Mild Alzheimer’s Disease in Participants on Solanezumab Versus Placebo Terminated/yes 3 To test the idea that solanezumab will slow the cognitive decline of Alzheimer’s Disease (AD) as compared with placebo in participants with
mild AD.		 ADAS-Cog14
NCT01127633 Solanezumab Continued Safety Monitoring of Solanezumab (LY2062430) in Alzheimer’s Disease Terminated/yes 3 This study is an open-label extension study in Alzheimer’s patients who have completed participation in either solanezumab Clinical Trial H8A-MC-LZAM (NCT00905372) or H8A-MC LZAN (NCT00904683). A summary of serious and other non- serious adverse events regardless of causality is located in the Reported Adverse Events module., Baseline through Week 104
NCT01739348 Verubecestat An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer’s Disease
(P07738)		 Terminated/yes BACE1 inhibitor 02-Mar This study assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks in the
treatment of Alzheimer’s Disease (AD).		 ADAS-Cog11
NCT01953601 Verubecestat Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer’s Disease (MK-8931-019) Terminated/yes 3 The study assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s Disease
(AD), also known as prodromal AD.		 Adverse events
NCT02910739 Verubecestat An Open-Label Study Investigating MK-8931 in Participants With Mild and Moderate Hepatic Insufficiency (MK-8931-016) Complete/yes 1 The purpose of this study is to compare the plasma pharmacokinetics of verubecestat (MK- 8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls.
NCT02569398 Atabecestat An Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer’s Dementia Terminated/No 2/3 The purpose of this study is to evaluate whether treatment with atabecestat slows cognitive decline compared with placebo treatment, as measured by a composite cognitive measure, the Preclinical Alzheimer Cognitive Composite (PACC), in amyloid- positive participants who are asymptomatic at
risk for developing Alzheimer’s dementia.
NCT02972658 Lanabecestat A Study of Lanabecestat (LY3314814)
in Early Alzheimer’s Disease		 Terminated/Yes 3 This study is an extension of study I8D-MC-
AZES (NCT02245737), the AMARANTH study.		 ADAS-Cog13
NCT02783573 Lanabecestat A Study of Lanabecestat (LY3314814) in Participants With Mild Alzheimer’s Disease Dementia Terminated/Yes 3 The main purpose of this study is to evaluate
the efficacy of the study drug known as lanabecestat in participants with mild Alzheimer’s disease (AD) dementia.		 ADAS-Cog13
NCT02245737 Lanabecestat An Efficacy and Safety Study of Lanabecestat (LY3314814) in Early Alzheimer’s Disease Terminated/Yes 2/3 The purpose of this study is to assess the efficacy and safety of lanabecestat compared with placebo administered for 104 weeks in the treatment of early Alzheimer´s disease. ADAS-Cog13
Table 2. Inflammation targeted therapies in Alzheimer’s Disease pipeline. (Data downloaded from clinicaltrials.gov/).
Table 2. Inflammation targeted therapies in Alzheimer’s Disease pipeline. (Data downloaded from clinicaltrials.gov/).
DRUG PHASE TARGET No of
participant		 duration OUTCOME
Inhibits the activation of microglia
Masatinib 3 TKI 600 24 weeks Recovered spetial learning performance and synaptic
markers (10)
AL002 2 TREM 2Antibody 265 96 weeks Diminished dystrophic neurites, lowered filamentous Aβ plaques, and encouraged microglia activation and Aβ phagocytosis
Monoclonal IgG1 antibody
NE3107 3 NFkB/ERK/ MAPK pw inhibitor 316 30 weeks Decreasing hyperglycemia, hyperinsulinemia, and
mediation of insulin resistance (12)
BCG 2 Immunomodulator 15 364 days BCG vaccination prevented cognitive impairment, raised circulating IFNγ, attracted macrophages to cerebral Aβ plaques, and boosted cerebral anti-inflammatory cytokines in a transgenic mouse model of AD (17)
Semaglutide 3 GLP-1 agonist 1840 173 weeks Anti-inflammatory in AD (cummings)
Baricitinib 1-2 JAK STAT inhibitor 20 24 weeks CSF concs of basatinib, CCL2
Canakimumab 2 Anti-interlukin 1b antibody 90 24 weeks Change in NTB total score
Daratumumab 2 Anti-CD38 antibody 15 24 weeks ADAS-cog11
Dasatinib+quercetin 2 SER kinase inhibitor and upregulator of SIRT1 and
senolytics		 48 48 weeks Adverse/serious events
20 11 weeks Safety and tolerability
12 12 weeks Neuro vascular, coupling, executive function, Gait speed
Sagramostim 2 Synthetic GM-CSF 42 24 weeks Adverse events
Senicapoc 2 KCA3,1 inhibitor 55 52 weeks ADAS-cog13 scores csf markers
Rapamycin 2 mTOR Inhibitor 10-40 8weeks/
12months		 BBB penetration, adverse events, metabolic pannel
Proleukin 2 Recombinant human
interleukin 2		 45 18 months CDR
Pepinemab 01-Feb Anti-SEMA4D antibody 40 40 weeks Adverse events
Montelukast 2 Leukotriene antagonist 70 26 weeks Global neuro physiological test battery
L-serine 2 Reduces inflammation 40 12 months Cognitive assessment, health check (blood tests), adverse
events
Lenatidomide 2 Proinflammatory cytokines
inhibitor		 30 18months ADAS-COG, ADAS-ADL
TB006 2 Anti-galactin 3 antibody 140 104 days Severity of dementia
T-Dap vaccine 01-Feb immunomodulator 50 6 months Change in abeta42/40 ratio and tau in plasma
Valacyclovir 2 HSV antiviral 120 18months
XProl 595 2 s-TNF inhibitor 201 23 weeks
CpG 1018 1 Actives TLR9 39 18 weeks Adverse events, rheumatoid factor, anti-nuclear antibody,
and anti-neutrophil ab in their blood
Emtricitabine 1 NRTI for HIV 35 8 months Adverse events
IBC-ab002 1 PD 1 inhibitor 40 48 weeks Abnormalities in brain, suicidal thoughts, vital signs,
significant changes in hematology
Salsalate 1 P300/CBP inhibitor 40 12 months Adverse events
VT301 1 Regulatory T cells 12 3 Adverse events
SYNAPTIC PLASTICITY
DRUGS
Blarcamesine 02-Mar Sigma 1/ muscarinic agonist 500 48 weeks
Simufilam 3 Binds to filamin to prevent interaction of abeta and A7 nicotinic acetylcholine
receptor		 750 52 weeks
AGB101 02-Mar SB2A INHIBITOR 164 78 weeks CDRSB
Fosgonimeton 02-Mar Hepatocyte growth
factor/MET activator		 475 26 weeks
Bryostatin 2 PKC activator 100 30 days SIB, safety
AL001 01-Feb GSK3 beta inhibitor 72 14 days Safety and toleralibity
Tertomotide 3 Telomerase RT mimic 936 6 month Sib, CDRSB
CY6463 2 Positive allostreric modulator of guanylate
cyclase		 30 14 days Safety and tolerability
Endonerpic 2 Specific target under defined may be collapsin response
mediator protein 2		 200 78 weeks Change in CSF p Tau 181
Dalzanemdor 2 N methyl d aspartate receptor, allosteric
modulator		 150 84 days
Elayta CT1812 2 Sigma 2receptor antagonist 450 18 months CDRSB
X039 2 Enhance n methyl d
aspartate receptor activity		 120 28 weeks
ExPlas 2 Human plasma with multiple
constituents		 60 1 year Adverse events
Levetiracetam 2 SV2A inhibitor 85 5 months
65 1 year
30 4 weeks Hippocampal function
MW150 2 MAPK P38alpha inhibitor 24 84 days Safety measures
Neflamapimod 2 MAPK P38alpha inhibitor 40 12 Weeks Brain inflammation by translocator protein tracer
Centella asiatica 1 Multimiodel herb derives traditional Chinese medicine 48 6 weeks Brain AA/CR ratio assessed by MR spectroscope
Table 3. p38MAPK inhibitors interventional therapy in Alzheimer’s Disease Pipeline (Data downloaded from clinicaltrials.gov/).
Table 3. p38MAPK inhibitors interventional therapy in Alzheimer’s Disease Pipeline (Data downloaded from clinicaltrials.gov/).
Drug Phase Study title Target NCT Study status/result Study summary Outcome measures
Neflamapimod 2 Proof-of-Concept Study of a
Selective p38
MAPK Alpha Inhibitor, Neflamapimod, in Subjects With Mild Alzheimer’s Disease		 P38 MAPK
inhibitor		 NCT03402659 Completed/ yes This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in subjects with mild Alzheimer’s disease. The primary objective is to demonstrate significant improvement relative to placebo-treatment in episodic memory function, as assessed by the Hopkins Verbal Learning Test. Secondary endpoints include Clinical Dementia Rating scale (CDR), Wechsler Memory Scale (WMS), Mini- Mental-Status-Examination (MMSE) and Cerebrospinal fluid (CSF) biomarkers of AD disease activity and progression. Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R), Combined change from baseline in z-scores of total and delayed recall on the Hopkins Verbal Learning Test - Revised (HVLT-R) in neflamapimod-treated subjects compared to placebo. The primary endpoint was analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD- specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate.For baseline total and delayed recall, a z- score for each subject is defined by z=(x-m)/s where x is the subject’s recall at baseline, and m and s are the overall mean and overall standard deviation of recall at baseline across all subjects. A composite baseline z-score for each subject is calculated using equal weighting in the following way: Z=0.5\*z-score for total recall at baseline + 0.5\*z- score for delayed recall at baseline. For HVLT-R, higher score indicates improvement., Baseline and 24 weeks
VX-745 2 Clinical Pharmacology of p38 MAP Kinase Inhibitor, VX- 745, in Mild Cognitive Impairment Due to Alzheimer’s Disease (AD) or
Mild AD		 P38 MAPK
inhibitor		 NCT02423200 Completed/ yes This study will assess the effects of VX-745 on markers of disease in the central nervous system of patients with MCI due to AD or with mild AD. The study will also evaluate the safety and tolerability of VX-745 in these patients during 6 weeks of dosing, as well as the plasma and cerebrospinal fluid concentrations of VX- 745 during dosing. Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines, Cytokines: Of nine cytokines assessed, only CSF IL-8 quantifiable at all time points. And so, only IL-8 levels are being reported herein. The analysis was exploratory and no statistical analysis was performed., Baseline and Day 42 of dosing with VX-745
VX-745 2 A PET Study of the Effects of p38 MAP Kinase Inhibitor, VX- 745, on Amyloid Plaque Load in Alzheimer’s Disease (AD) P38 MAPK
inhibitor		 NCT02423122 Completed/ yes This study will assess the effects of administration of VX-745 for 12 weeks on amyloid plaque burden in Alzheimer’s disease (AD). Subjects who meet entry criteria will undergo 11C-PiB (Carbon-11-labeled Pittsburgh Compound B) positron emission tomography (PET) at baseline and after 45 days of dosing with VX-745. Cognitive testing will also be conducted at baseline and day 45. Percent Change From Baseline in Amyloid Plaque Burden by 11C-PiB PET, Percent change in global cortical amyloid specific PET signal (BPND), Baseline compared to following
12 weeks’ dosing with VX-745|Number of 11C-PiB Responders, Number of patients meeting protocol pre- specified definition of response: \> 7% reduction in global cortical BPND, Day 84
Exantide 2 A Pilot Clinical Trial of Exendin-4 in Alzheimer’s Disease P38 MAPK
inhibitor		 NCT01255163 terminated Researchers were interested in studying the safety and comparing the effects of Exendin-4 with placebo on cognitive performance, clinical progression of dementia, various chemicals measured in blood and cerebrospinal fluid, and brain MRI, in individuals with early-stage Alzheimer’s disease or MCI. Objectives were to determine the safety and tolerability of twice daily administration of Exendin-4, as well as to acquire preliminary evidence for effects on cognitive performance, clinical progression of dementia, various chemicals measured in blood and cerebrospinal fluid, and brain MRI, in individuals with early-stage Alzheimer’s disease or mild cognitive impairment. * Eligible participants were divided into two groups (double-blind randomization). One group received Exendin-4 SC twice daily, and the other will received a placebo. Participants kept a medication diary and scheduled for additional study visits 1 and 2 weeks after the start of the treatment. Participants had regular followup visits with blood tests, cognitive tests, imaging studies, and other examinations 6, 12, and 18 months after the start of the treatment. Another lumbar puncture was performed optionally at the 18- month followup visit. Number of Participants With Incidence of Nausea, Tolerability of exenatide (nausea is the most common expected adverse event of exenatide), 18 months
Minocycline 2 Minocycline in Patients With Alzheimer’s Disease P38 MAPK
inhibitor		 NCT01463384 completed Cognitively normal individuals, patients with Mild Cognitive Impairment (MCI) or Alzheimer’s Disease (AD) will undergo clinical screening, neuropsychological tests, blood and urine analyses, quantitative magnetic resonance imaging (MRI) and proton (1H ) and carbon 13 (13C) magnetic resonance spectroscopy (MRS). Each individual will receive minocycline oral administration for 4 weeks initially, after which MRI, MRS and neuropsychological results will be recorded. If no adverse side effects occur, subjects will continue minocycline administration for an additional 5 months. Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration., Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged)|Hippocampal Volumes Measured in three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age- matched Controls (NC)., Using magnetic resonance images acquired, hippocampal volume was measured monthly for 6 months. Biomarkers NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC).two biomarkers, N acetylaspartate (NAA, a neuronal marker) and myo-inositol (mI, a glial marker) were quantified and then used to calculate NAA/mI (an index currently widely used for AD and MCI diagnosis). Scale of MRS biomarkers for aged- matched controls: NAA = 1.43, mI = 0.60, NAA/mI = 2.38. Any value lower than NAA/mI of 2.38 are considered not
normal.
MW150 2 MW150 Stress Kinase Inhibitor in Mild to Moderate Alzheimer’s Disease P38 MAPK
inhibitor		 NCT05194163 Not yet recruiting This study is a phase 2a randomized double-blind,
placebo-controlled, study, in mild-to-moderate Alzheimer’s disease, of the oral investigational drug MW150, a p38alphaMAPK kinase inhibitor. The primary goals of this study are to investigate the safety and tolerability, and drug movements in the body. The secondary goals of the study are to investigate the effects of the drug on cognitive performance, activities of daily living, and behavior, and the biological effects of the drug on blood biomarkers.		 Drug Safety- Blood tests, Number of participants with
treatment-related adverse events as assessed by laboratory test abnormalities., 84 days treatment|Drug Safety- Electrocardiographic, Number of participants with emergent abnormal electrocardiograms., 84 days treatment|Drug Safety- C-SSRS, Development of any suicidality on COLUMBIA-SUICIDE SEVERITY RATING SCALE
(C-SSRS) score (minimum 0, no maximum, higher number worse)., 84 days treatment|Drug Tolerability- Adverse events, Incidence of adverse events (AE)., 84 days treatment.
Mastinib 3 Masitinib in
Patients With
Mild to
Moderate Alzheimer’s Disease		 TKI NCT05564169 Not yet recruiting/N o Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB21004 will evaluate masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate Alzheimer’s disease. Absolute change from baseline in ADAS-Cog-11 score, Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog) (scores range from 0 to 70, with higher scores indicating worse dementia), 24 weeks|Absolute change from baseline in ADCS-ADL score, Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) (scores from 0 to 78, with lower scores
indicating worse function), 24 weeks
Nilotinib 3 Evaluating the
Efficacy and
Safety of
Nilotinib BE in Subjects With Early Alzheimer’s Disease		 TKI NCT05143528 Not yet recruiting/N o This study will investigate the safety and efficacy of a Tyrosine Kinase Inhibitor (TKI) called Nilotinib BE (bioequivalent) in individuals with Early Alzheimer’s disease (EAD). This is a multi-center double blinded, Phase 3 study, that will enroll patients for three years in approximately 50 centers nationwide. The total duration of the study will be for five years. Changes From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 72 [ Time Frame: Baseline, Week 72], CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following a systematic patient examination, the rater assigns a score describing the participant’s current performance level in each of these domains of life functioning. Prespecified severity anchors range from none
= 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). "Sum of boxes" scoring methodology sums the score for each of the 6 domains and provides a value ranging from 0 to 18 that can change in increments of 0.5 or greater. Higher scores indicate greater disease severity. A positive change from baseline indicates clinical decline., 72 weeks
Bumetanide 2 Bumetanide in Patients With Alzheimer’s Disease NCT06052163 Not yet recruiting/No Bumetanide is a potent diuretic administered orally and is FDA approved for the treatment of edema and hypertension. Repurposing bumetanide as a medication for AD has been proposed based on data that demonstrated its ability to "flip" the APOE genotype-dependent transcriptomic signatures in AD mouse and cell culture models. Critically, this discovery was subsequently explored in Electronic Health Record cohorts, which revealed that among individuals over the age of 65, bumetanide exposure was significantly associated with a lower prevalence of AD in three
independent datasets.		 Incidence of Treatment-Related Adverse Events, Number of participants with adverse events including clinical signs and symptoms, change in vital signs, ECGs, laboratory safety tests, and suicidality assessments., 6 months
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