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Cited by 30Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Current therapeutics for Alzheimer’s disease and clinical trials

Open access
Xiao, Danqing, Zhang, Chen·2024·Exploration of Neuroscience
DOI 10.37349/en.2024.00048
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Abstract

Alzheimer’s disease (AD) is a major type of dementia and neurodegenerative disease, characterized by memory loss and cognitive decline. Over decades, significant efforts have been dedicated to finding its cause, pathogenic mechanisms, biomarkers for early detection, and clinical trials for its treatment. Earlier approved drugs mainly ameliorated the symptoms of AD, until recent years when two drugs targeting amyloid-beta (Aβ) protein were approved to slow down the progression of the disease. This review article encompasses the history of drug development in treating AD and clinical trials that failed and succeeded. Clinicaltrials.org website was systematically searched and screened for randomized controlled trials with results posted in the past 10 years. Among the 3,388 AD clinical trials, 211 interventional studies registered under AD have met eligibility. This review includes the interventional targets for drug discovery such as Aβ, tau, neurotransmitter receptors, neuroinflammation, multi-target studies, repurposing pharmacological agents, non-pharmacological interventions, and clinical therapy development for the neuropsychiatric symptoms of dementia. Current clinical trials are ongoing and no results are available as of yet. With the vast choices of drug targets that have been investigated, this review aims to present some insights into future AD drug design and trials and contribute to our ongoing efforts to find the cure.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes approved symptomatic and anti-amyloid therapies for Alzheimer’s disease (AD) and surveys clinical trials targeting Aβ, tau, neurotransmitter receptors, neuroinflammation, multi-target agents, repurposing, non-pharmacological interventions, and neuropsychiatric symptoms. It reports 3,388 AD trials overall and 211 interventional trials with posted results from the past decade, while ongoing trials have no results yet.

Key findings

  • Approved treatments include acetylcholinesterase inhibitors (donepezil approved earliest, in 1996; also rivastigmine, galantamine, memantine, tacrine), memantine (2003) for moderate-to-severe AD, and anti-amyloid monoclonal antibodies aducanumab and lecanemab for MCI to early AD; lecanemab showed 27% slower cognitive decline in the CLARITY AD trial.
  • ClinicalTrials.gov screening identified 3,388 AD clinical trials total, 2,030 studies starting from 01/01/2015, 1,596 interventional studies, and 211 trials with results: phase 1 n = 32, phase 2 n = 78, phase 3 n = 37, phase 4 n = 4, as reported.
  • Many Aβ-targeting trials failed, including BACE inhibitors, γ-secretase inhibitors, and first/second-generation anti-amyloid antibodies; third-generation antibodies aducanumab, donanemab, and lecanemab target plaque clearance, with donanemab reducing CSF amyloid and plasma P-tau/T-tau and meeting IADRS in early AD with low tau.
  • Tau immunotherapies and multi-target/combination approaches are under investigation; AADvac1 was safe but lacked efficacy in phase 2 overall, though post hoc subgroups showed slowed CDR-SB/ADL decline, and UB-311 produced a 100% antibody response with 14% microhemorrhages.

Methods

  • Narrative review of AD therapeutics and clinical trials; the authors systematically searched ClinicalTrials.gov and screened randomized controlled trials with results posted in the past 10 years.
  • Trials were limited to those starting from 01/01/2015; from 2,030 studies, observational/registry studies were excluded, leaving 1,596 interventional studies, and after keeping trials with results, 211 remained.
  • The review covers interventional targets including Aβ, tau, neurotransmitter receptors, neuroinflammation, growth factors, hormones, multi-target studies, repurposed agents, non-pharmacological interventions, and neuropsychiatric symptom trials; no meta-analysis is described.

Limitations

  • Stated in the paper: current clinical trials are ongoing and no results are available as of yet.
  • Evident from the text: as a narrative review, no formal systematic review, meta-analysis, risk-of-bias assessment, or quantitative synthesis is described.
  • Evident from the text: the trial survey was restricted to interventional studies with posted results from 2015 onward, which may exclude unpublished, negative, or ongoing trials and limits generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.37349/en.2024.00048

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 71 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    Among 3,388 Alzheimer's disease clinical trials, 211 interventional studies registered under Alzheimer's disease met eligibility.

    “Among the 3,388 AD clinical trials, 211 interventional studies registered under AD have met eligibility.”
    Quote in the paperNot a substantial claim
  • Findingnone given
    § Introduction

    Focusing on trials starting from 01/01/2015 and encompassing the past 10 years includes 2,030 studies.

    “We chose to focus on the trials starting from 01/01/2015 and encompassing the past 10 years, including 2,030 studies.”
    Quote in the paperSubstantial claim
  • Findingreasoning
    § Introduction

    After excluding observational studies and keeping all interventional clinical trials, there are 1,596 studies registered under Alzheimer's disease.

    “After excluding observational studies (with patient registries), and keeping all the interventional clinical trials, there are 1,596 studies registered under AD.”
    Quote in the paperNot a substantial claim
  • Premisenone given
    § Introduction

    The rationales of early Alzheimer's disease drug trials from 2011 to 2020 are based on the amyloid-beta hypothesis.

    “The rationales of these early AD drug trials from 2011 to 2020 are based on the Aβ hypothesis.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Introduction

    Two consecutive multicenter phase 2a trials show that blarcamesine improves cognition dose-dependently in MMSE and ADCS-ADL in subjects with mild-to-moderate Alzheimer's disease.

    “Two consecutive multicenter phase 2a trials, randomized and open-label, show it improves cognition, dose-dependently, in mini-mental status examination (MMSE) and AD Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) in subjects with mild-to-moderate AD [30].”
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    Findingnone given
    § Introduction

    The included trials were or are in the process of being carried out globally.

    “These trials were or are in the process of being carried out globally.”
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    Findingreasoning
    § Introduction

    After keeping trials with results, 211 studies remain: phase 1 n = 32, phase 2 n = 78, phase 3 n = 37, and phase 4 n = 4.

    “After keeping the trials with results (excluding the ones without results), 211 studies remain with (early) phase 1 (n = 32), phase 2 (n = 78) trials on the safety and tolerability test, and phase 3 (n = 37) and phase 4 (n = 4) trials on slowing the cognitive decline.”
    Quote in the paperSubstantial claim

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    Findingcitation
    § Introduction

    As of May 2024, there are a total of 3,388 Alzheimer's disease clinical trials including all studies.

    “As of May 2024, there are a total of 3,388 Alzheimer’s disease clinical trials including all studies (clinicaltrials.gov).”
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    Findingnone given
    § Introduction

    The majority of clinical trials target intervention with Alzheimer's disease therapeutic agents at early/mild to moderate stages and early detection.

    “The majority of clinical trials are targeting intervention with AD therapeutic agents at early/mild to moderate stages of AD, and its early detection.”
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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given
    § Abstract

    Earlier approved drugs mainly ameliorated the symptoms of Alzheimer's disease, whereas two drugs targeting amyloid-beta protein were approved in recent years to slow disease progression.

    “Earlier approved drugs mainly ameliorated the symptoms of AD, until recent years when two drugs targeting amyloid-beta (Aβ) protein were approved to slow down the progression of the disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Introduction

    Ladostigil is a hybrid molecule combining the carbamate group of rivastigmine and the N-propargyl group of monoamine oxidase inhibitors, but it failed to meet the primary endpoint of delaying cognitive impairment in phase 2.

    “Ladostigil is a hybrid molecule combining the carbamate group of rivastigmine and the N-propargyl group of monoamine oxidase (MAO) inhibitors, though it failed to meet the primary endpoint of delaying cognitive impairment in phase 2.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Introduction

    Memantine is more effective in providing cognitive and behavioral benefits and is approved for patients with moderate to severe Alzheimer's disease as monotherapy or combination therapy with donepezil.

    “Memantine is more effective in providing cognitive and behavioral benefits and approved for patients with moderate to severe AD as monotherapy or combination therapy with donepezil [9, 12].”
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    Premisecitation
    § Introduction

    Approaches targeting oxidative stress linked to mitochondrial dysfunction are used to screen neuroprotective antioxidant compounds in cells and mouse models of Alzheimer's disease.

    “Moreover, there are other important approaches, for example, the exploration and efforts targeting oxidative stress linked to mitochondria dysfunction to screen neuroprotective antioxidant compounds in cells and mouse models of AD [16, 17, 19].”
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    Interpretationnone given
    § Introduction

    Combination therapy that improves symptoms plus disease-modifying therapeutics would modify and slow down the progression of Alzheimer's disease as add-on treatments in combination with current drugs.

    “Combination therapy that improves symptoms plus disease-modifying therapeutics (DMT) would modify and slow down the progression of AD as add-on treatments in combination with the current drugs.”
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    Premisecitation
    § Introduction

    These early Alzheimer's disease drug trials resulted in failure due to lack of efficacy and/or side effects of toxicity.

    “These trials resulted in failure due to lack of efficacy and/or side effects of toxicity, for example [31] (Table 2).”
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    Premisecitation
    § Introduction

    Memantine is both a non-competitive NMDA receptor antagonist and a dopamine agonist for moderate to severe Alzheimer's disease.

    “Finally, memantine is both a non-competitive NMDA receptor antagonist and a dopamine agonist for moderate to severe AD [11].”
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    § Introduction

    MAOB activity is increased in Alzheimer's disease at reactive astrocytes near amyloid plaques.

    “MAOB activity is increased in AD at reactive astrocytes near amyloid plaques.”
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    Premisenone given
    § Introduction

    J-147 under phase 1 is a multi-target drug including targets such as MAO.

    “J-147 under phase 1 is a multi-target drug including targets like MAO.”
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    Premisecitation
    § Introduction

    Amyloid-beta clearance by immunotherapy was first demonstrated in an ischemic mouse model showing amyloid plaques can disappear with injections of human beta-amyloid-(1-42)-peptide for some months.

    “Aβ clearance by immunotherapy was first demonstrated in an ischemic mouse model showing amyloid plaques can disappear with injections of human β-amyloid-(1-42)-peptide for some months [33].”
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    Premisenone given
    § Introduction

    Lumateperone and idolopiridine targeted both 5-HT6 and acetylcholinesterase, and both were discontinued due to lack of efficacy.

    “Lumateperone and iolopiridine targeted both 5-hydroxytryptamine 6 (5-HT6) and AchE, though both were discontinued due to lack of efficacy.”
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    Premisecitation
    § Introduction

    Rivastigmine patch or oral capsule is the only acetylcholinesterase inhibitor that provides inhibition for both acetylcholinesterase and butyrylcholinesterase and shows efficacy and safety in relieving cognitive symptoms of Alzheimer's disease.

    “Among them, a rivastigmine patch or oral capsule is the only acetylcholinesterase inhibitor (ACEI) that provides inhibition for both acetylcholinesterase and butyrylcholinesterase and shows efficacy and safety in helping to relieve the cognitive symptoms of AD (e.g., [13]).”
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    Study design and conductnone given
    § Abstract

    Clinicaltrials.org was systematically searched and screened for randomized controlled trials with results posted in the past 10 years.

    “Clinicaltrials.org website was systematically searched and screened for randomized controlled trials with results posted in the past 10 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Introduction

    Passive immunotherapies with monoclonal antibodies against amyloid-beta went through three generations of development, with FDA approval of two drugs for mild cognitive impairment to early stage Alzheimer's disease.

    “Passive immunotherapies with monoclonal antibodies against Aβ in clinical trials went through three generations of development [11, 34], with FDA approval of two drugs for MCI to early stage of AD.”
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    Premisecitation
    § Introduction

    These drugs are used for all stages of Alzheimer's disease, but inhibition of cholinesterase enzymes works best at the early stage.

    “These drugs are used for all stages of AD, but inhibition of cholinesterase enzymes works best at the early stage of AD [9, 12].”
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    Premisecitation
    § Introduction

    Current therapeutics targeting the NMDA receptor prevent Ca2+-induced excitotoxicity, and memantine was approved for this purpose in 2003.

    “Current therapeutics to ameliorate and control the cognitive and behavioral symptoms by targeting the NMDA receptor prevent Ca2+ induced excitotoxicity [2, 9–11], and memantine was approved for this purpose in 2003.”
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    § Introduction

    Anti-inflammatory therapy is intended to reduce the harmful inflammatory response of microglia activation in the Alzheimer's disease brain.

    “Anti-inflammatory therapy is intended to reduce the harmful inflammatory response of microglia activation in the AD brain [16–18].”
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    Premisecitation
    § Introduction

    The FDA has approved two drugs, aducanemab and lecanemab, for mild cognitive impairment to early mild stages of Alzheimer's disease after years of failed clinical trials, with aducanemab receiving accelerated approval.

    “The FDA has approved two drugs for mild cognitive impairment (MCI) to early, mild stages of AD after years of failed clinical trials. They are aducanemab, and lecanemab, among which aducanemab received accelerated approval [14, 15].”
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    § Introduction

    Five drugs-donepezil, rivastigmine, galantamine, memantine, and tacrine-are approved on the market, with donepezil approved earliest in 1996.

    “Five drugs (donepezil, rivastigmine, galantamine, memantine, and tacrine) are approved on the market with donepezil approved the earliest, in 1996.”
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    Premisecitation
    § Introduction

    Blarcamesine combines agonist activities at the muscarinic M1 receptor, NMDA receptor, and sigma-1 receptor, targets tau protein, and reduces Alzheimer's disease neurodegeneration.

    “Blarcamesine, combining agonist activities at the muscarinic M1 receptor, the NMDA receptor, and the sigma-1 receptor, targets protein tau and reduces AD neurodegeneration [29].”
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    Premisecitation
    § Introduction

    Probiotics improved cognitive performance and metabolic profiles in AD, possibly by reducing intestinal inflammation and oxidative stress, in randomized double-blind controlled trials and their meta-analysis.

    “Randomized double-blind controlled clinical trials and their meta-analysis showed that probiotics improved cognitive performance and metabolic profiles in AD possibly by reducing intestinal inflammation and oxidative stress [64, 67].”
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    Premisecitation
    § Introduction

    Brain stimulation with a computer program showed a trend to increase cognitive function and reduce depression in mild to moderate AD in a terminated trial (NCT 03656107).

    “Brain stimulation with a computer program showed a trend to increase cognitive function and reduce depression in mild to moderate AD in a terminated trial (due to COVID-19) (NCT 03656107) [68].”
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    § Introduction

    In 2024, the marketing of aducanumab was discontinued by the manufacturer.

    “In 2024, the marketing of aducanumab was discontinued by the manufacture.”
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    § Introduction

    Overall, lecanemab significantly reduced amyloid burden with modestly less decline in measures of cognition and function in early-stage Alzheimer's disease patients.

    “Overall, lecanemab significantly reduced amyloid burden with modestly less decline in measures of cognition and function in early-stage AD patients [34, 39, 43].”
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    § Introduction

    Nutraceutical huperzine A has shown benefits in improving cognitive function, memory function, and daily living activities by reducing oxidative stress.

    “Nutraceutical huperzine A has shown benefits in improving cognitive function, memory function, and daily living activities by reducing oxidative stress [65].”
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    § Introduction

    Namzaric, a fixed-dose combination of donepezil and memantine, is used for the treatment of AD patients with moderate to severe AD dementia.

    “For example, Namzaric, a fixed dose-combination of donepezil and memantine, is used for the treatment of AD patients with moderate to severe AD dementia [9].”
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    § Introduction

    Aerobic exercise for 26 weeks increased glucose metabolism and improved executive function in AD (NCT 02384993).

    “Aerobic exercise for 26 weeks increased glucose metabolism and improved executive function (NCT 02384993) [62].”
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    § Introduction

    Intermittent calorie restriction in women with insulin resistance significantly reduced the CSF Aβ42/Aβ40 ratio and reduced tau (NCT 02460783).

    “The result showed a significant reduction of the CSF Aβ42/Aβ40 ratio and reduction of tau (NCT 02460783).”
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    § Introduction

    Social dance movement and exercise with treadmill walking for people with MCI or early stage of AD and other dementia significantly improved multiple brain network characteristics, global efficiency, modularity, quality of life, and balance (NCT 03333837).

    “Social dance movement and exercise with treadmill walking for people with MCI or early stage of AD and other dementia significantly improved multiple brain network characteristics, global efficiency, modularity, quality of life, and balance (NCT 03333837) [63].”
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    § Introduction

    Four aducanumab phase 3 trials against amyloid-beta fibrils were carried out; two were terminated due to futility analysis, and two trials (ENGAGE and EMERGE) showed benefit by reducing Alzheimer's disease biomarkers, amyloid-beta and tau proteins, in early-onset Alzheimer's disease in certain patients.

    “Four aducanumab phase 3 trials against Aβ fibrils were carried out; two were terminated due to futility analysis, and two trials (ENGAGE and EMERGE) showed benefit by reducing AD biomarkers, Aβ and tau proteins, in early-onset AD in certain patients [9].”
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    § Introduction

    Omega-3 fatty acid supplements have shown benefits in improving memory in subjects with MCI, probably linked to cardiovascular benefits.

    “Clinical trials with omega-3 fatty acids supplements have shown benefits in improving memory probably in link to its cardiovascular benefits in subjects with MCI [11, 66].”
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    Interpretationcitation
    § Conclusions

    Current multiple ongoing anti-tau immunotherapies are working on improving safety and efficacy and might provide a cheaper, affordable, and more efficacious approach in the future compared to currently approved anti-amyloid therapy against AD.

    “current multiple ongoing anti-tau immunotherapies are working on improving safety and efficacy and might provide a cheaper affordable, and more efficacious approach in the future, compared to currently approved anti-amyloid therapy against AD.”
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    § Introduction

    Lemborexant (Dayvigo), an orexin receptor antagonist, is approved for insomnia, lower nighttime activity, and improved circadian rhythmicity in mild-moderate AD (NCT 03001557).

    “Lemborexant (Dayvigo) Orexin receptor antagonist Completed (2016–2020) Mild-moderate Approved for insomnia, lower nighttime activity, and improved circadian rhythmicity 03001557”
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    § Introduction

    Pimavanserin produced a delay in psychosis relapse (p < 0.05) and a lower risk of relapse with continuation of the drug in probable AD with agitation and aggression (NCT 03118947, NCT 03325556).

    “Pimavanserin (Nuplazid) Inverse agonist and antagonist of 5-HT2A in neurotransmission Completed phase 2 (2017–2019) Probable AD who has symptoms of agitation and aggression (1) Promising reduction of psychosis score in AD, also see [ 74 ] and (2) delay in psychosis relapse ( p < 0.05) and a lower risk of relapse with the continuation of the drug [ 75 ] 03118947 03325556”
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    § Introduction

    Apathy is the most prevalent disorder among the neuropsychiatric symptoms of AD.

    “the most prevalent disorder among the neuropsychiatric symptoms of AD [73]”
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    § Introduction

    Transcranial direct current stimulation (tDCS) improved cognition and behavior, with a significant interaction between default mode network (DMN) and salient network and functional connectivity changes in a polarity-dependent effect.

    “On the other hand, transcranial direct current stimulation (tDCS) improved cognition and behavior, with a significant interaction between default mode network (DMN) and salient network and functional connectivity changes in a polarity-dependent effect [72].”
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    § Introduction

    Suvorexant (Belsomra, MK-4305), an orexin receptor antagonist, is approved for insomnia in AD and lengthened total night sleep time in mild-moderate AD (NCT 02750306).

    “Suvorexant (Belsomra, MK-4305) Orexin receptor antagonist Completed (2016–2018) Mild-moderate Approved for insomnia in AD, lengthened total night sleep time 02750306”
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    Premisecitation
    § Introduction

    Gamma stimulation with light flicker (gamma entrainment using sensory stimulus or GENUS) reduced phosphorylated tau and amyloid in an AD mouse model.

    “Similarly, investigators sought to replicate the finding from the AD mouse model study that gamma stimulation with light flicker (gamma entrainment using sensory stimulus or GENUS) reduced phosphorylated tau and amyloid with combined visual and auditory GENUS in the medial prefrontal cortex [71].”
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    Premisenone given
    § Introduction

    Lemborexant (Dayvigo) and suvorexant (Belsomra, MK-4305), antagonizing the orexin receptor, are approved for insomnia in mild to moderate AD.

    “Lastly, lamborexant (Dayvigo) and suvorexant (Belsomra, MK-4305) antagonizing the orexin receptor are approved for insomnia in mild to moderate AD.”
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    Interpretationreasoning
    § Conclusions

    Combination therapies targeting multiple pathways or multiple aspects of the same pathway may be the key to effective AD treatment and precision individualized medicine.

    “Combination therapies targeting multiple pathways or multiple aspects of the same pathway may be the key to effective AD treatment and “precision” individualized medicine.”
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    • Rests on an assumption: Combination drug therapy targeting two or more different targets may have a synergistic effect on therapeutic outcomes.

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    Premisecitation
    § Conclusions

    Tau proteins correlate with AD more closely than amyloid proteins and participate in the spreading of the disease.

    “Considering that tau proteins correlate with AD more closely than amyloid proteins and participate in the spreading of the disease [51], current multiple ongoing anti-tau immunotherapies are working on improving safety and efficacy and might provide a cheaper affordable, and more efficacious approach in the future, compared to currently approved anti-amyloid therapy against AD.”
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    Interpretationnone given
    § Conclusions

    Targeting both Aβ and tau pathways could be promising for development of effective therapeutic interventions.

    “Further, the interplay between Aβ and tau pathology remains to be known, and targeting both pathways could be promising for development of effective therapeutic interventions.”
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    • The authors state this as an assumption: The interplay between Aβ and tau pathology remains unknown.

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    Premisenone given
    § Introduction

    Pimavanserin (Nuplazid), an inverse agonist and antagonist of 5-HT2A in serotonin neurotransmission, shows promising reduction of psychosis.

    “Pimavanserin (Nuplazid), an inverse agonist and antagonist of 5-HT2A in serotonin neurotransmission, shows promising reduction of psychosis.”
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  • The paper relies on this without support.

    ClinicalTrials.gov records are complete and accurate enough to enumerate Alzheimer’s disease trials and their results.

    “As of May 2024, there are a total of 3,388 Alzheimer’s disease clinical trials including all studies (clinicaltrials.gov).”

  • The paper relies on this without support.

    Restricting to trials starting in 2015 and with posted results yields a representative sample of current Alzheimer’s disease clinical trials.

    “We chose to focus on the trials starting from 01/01/2015 and encompassing the past 10 years, including 2,030 studies.”

  • The authors state this as an assumption.

    The Common Alzheimer’s and Related Dementias Research Ontology (CADRO) framework is suitable for categorizing Alzheimer’s disease therapeutic targets.

    “clinical therapy development for the neuropsychiatric symptoms of dementia based on Common Alzheimer’s and Related Dementias Research Ontology (CADRO).”

  • The paper relies on this without support.

    The results reported in the included trial registrations or publications are valid.

    “After keeping the trials with results (excluding the ones without results), 211 studies remain”

  • The paper relies on this without support.

    Combination drug therapy targeting two or more different targets may have a synergistic effect on therapeutic outcomes.

    “Considering the complexity of AD pathogenesis, using combination drug therapy on two or more different targets presents the potential for improved efficacy and outcomes, as targeting multiple pathways or mechanisms might have a synergistic effect on therapeutic outcomes.”

  • The authors state this as an assumption.

    The interplay between Aβ and tau pathology remains unknown.

    “Further, the interplay between Aβ and tau pathology remains to be known”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • AN-1792 was withdrawn during Phase II of the trial due to side effects associated with meningoencephalitis, reported in 6% of patients.

    “However, AN-1792 was withdrawn during Phase II of the trial due to side effects associated with meningoencephalitis, which were reported in 6% of patients [140,141,142,143,144].”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [143]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The same trial identifiers are assigned conflicting phases and agents

    Minor

    Both listed NCT identifiers appear under neflamapimod as phase 2 trials and under semagacestat as phase 3 trials.

  • LY3202626 is assigned conflicting secretase targets

    Minor

    The table describes LY3202626 as reducing β-secretase activity, while the clinical-trials discussion lists it as an example of gamma-secretase inhibition.

2 of 2

Cites

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Cited by

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Related

Authors
Xiao, D., & Zhang, C.
Affiliations
  • Regis College (US)
  • Capital Medical University (CN)
Corresponding author
  • Xiao, Danqing
  • Zhang, Chen
ORCID
Venue
Exploration of Neuroscience
Publisher
Open Exploration Publishing
Published
2024-06-27
Volume
3
Issue
3
Pages
255-271
ISSN
2834-5347 (ISSN-L)
DOI
10.37349/en.2024.00048
OpenAlex
W4400098412
Semantic Scholar
03dbf11e528ff3cb0118f91fb115ab857e438485
Cited by
30
References
76
Citations by year
2026: 15 · 2025: 13 · 2024: 2
FWCI
8.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Exploration of neuroscience (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, Alzheimer's disease therapeutics, amyloid-beta, tau protein, therapeutic target, drug repurposing, neuroinflammation, neurotransmitter receptors, multi-target drugs, clinical trials, drug development history

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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