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Cited by 966Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Current and Future Treatments in Alzheimer Disease: An Update

Open access
Yiannopoulou, Konstantina G, Papageorgiou, Sokratis G·2020·Journal of Central Nervous System Disease
DOI 10.1177/1179573520907397PMC PMC7050025
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Abstract

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes current FDA-approved symptomatic treatments for Alzheimer disease and the 2019 pipeline of disease-modifying and symptomatic agents. It emphasizes that no disease-modifying therapy is approved and that future treatment may move toward biomarker-guided precision medicine.

Key findings

Current approved pharmacotherapy remains symptomatic: the 3 AChEIs donepezil, galantamine, and rivastigmine plus the NMDA antagonist memantine; no new FDA drug for AD has been approved since 2003 and there are no approved DMTs.

  • A clinicaltrials.gov search accessed August 19, 2019 found 165 recruiting or active-but-not-recruiting phase 1–3 AD trials; the February 2019 pipeline review cited found 132 agents in 156 trials (28 drugs in 42 phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials), classified as 73% DMTs, 13% symptomatic cognitive enhancers, and 11% for BPSD.
  • Anti-amyloid failures include semagacestat, bapineuzumab, solanezumab, and the BACE inhibitors lanabecestat, verubecestat, and atabecestat; BACE inhibitors reduced CSF Aβ42 dose-dependently but without cognitive or functional benefit.
  • Tau-directed agents remain earlier-stage: only 1 tau-related agent was in phase 2/3, 10 in phase 2, and 5 in phase 1; other DMT mechanisms include neuroprotection, anti-inflammatory effects, growth factor promotion, metabolic effects, and stem cell therapies.

Methods

Design: narrative review of current nonpharmacological and pharmacological AD management, FDA-approved medications, BPSD treatments, and phase 1–3 investigational agents.

  • Data/sample: literature review plus a clinicaltrials.gov search for recruiting or active-but-not-recruiting phase 1–3 AD trials accessed August 19, 2019 (165 outcomes), and citation of the February 2019 AD drug development pipeline review (132 agents in 156 trials).
  • Analysis: narrative synthesis and classification of agents by proposed mechanism—amyloid-related, tau-related, other DMT mechanisms, and symptomatic—without a formal systematic review or meta-analysis described.

Limitations

Stated: no effective treatment options and no approved DMTs exist; many trial failures are attributed to starting therapy too late, inappropriate drug doses, wrong treatment targets, inadequate understanding of AD pathophysiology, and variability in diagnostic markers and endpoints.

  • Evident from the text: this is a narrative review without a stated systematic search strategy, inclusion/exclusion criteria, or risk-of-bias assessment.
  • Evident from the text: pipeline findings are a cross-sectional 2019 snapshot and efficacy claims for many agents are brief, based on cited trials or conference reports rather than independent quantitative synthesis.

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

Integrity signals

Registry

Crossref · 10.1177/1179573520907397

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 223 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A search for phases 1, 2, and 3 recruiting or active but not recruiting clinical trials for Alzheimer disease in clinicaltrials.gov (accessed August 19, 2019) showed 165 outcomes.

    “A search for phases 1, 2, and 3 “recruiting” or “active but not recruiting” clinical trials for AD in clinicaltrials.gov (accessed August 19, 2019) showed 165 outcomes.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    At the moment, there are no effective treatment options for Alzheimer disease.

    “However, despite all arduous research efforts, at the moment, there are no effective treatment options for the disease.3,4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Scheltens P Blennow K Breteler MMB, et al Alzheimer’s disease. Lancet. 2016; 388: 505- 517. 26921134 source

      Not checked in the free run.

    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • Premisecitation

    Patients who started an acetylcholinesterase inhibitor 6 months later showed more rapid cognitive decline than those who started the drug immediately.

    “Initiation of AChEI treatment as soon as possible after the diagnosis is preferred as patients who started the AChEI 6 months later showed more rapid cognitive decline than those who started the drug immediately.17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Farlow M Anand R Messina J Hartman R Jr Veach J A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000; 44: 236- 241. 11096224 source

      Not checked in the free run.

  • Premisecitation

    The elements of the amyloid cascade include local inflammation, oxidation, excitotoxicity (excessive glutamate), and tau hyperphosphorylation.

    “The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate), and tau hyperphosphorylation.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • Premisecitation

    Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters and to the cognitive deficiencies seen in Alzheimer disease.

    “Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (eg, acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

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  • May combine two claims. 78
  • Classified as probably not a substantial claim. 16
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisereasoning

    Acetylcholinesterase inhibitors are contraindicated in severe cardiac arrhythmias, especially bradycardia or syncope, active peptic ulcer or gastrointestinal bleeding history, and uncontrolled seizures.

    “Thus, AChEIs are contraindicated in conditions including severe cardiac arrhythmias, especially bradycardia or syncope. They are also contraindicated in active peptic ulcer or gastrointestinal bleeding history and uncontrolled seizures.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Farlow M Anand R Messina J Hartman R Jr Veach J A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000; 44: 236- 241. 11096224

      Not checked in the free run.

    • cites [18] Rountree SD Atri A Lopez OL Doody RS Effectiveness of antidementia drugs in delaying Alzheimer disease progression. Alzheimers Dement. 2013; 9: 338- 345. 23102979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neurotoxicity is mainly attributed to the forming of amyloid oligomers, which initiates the amyloid cascade.

    “It is the forming of amyloid oligomers to which neurotoxicity is mainly attributed and initiates the amyloid cascade.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Memantine binds preferentially to open NMDA receptor-operated calcium channels, blocking NMDA-mediated ion flux and ameliorating dangerous effects of pathologically elevated glutamate levels.

    “Memantine binds preferentially to open NMDA receptor–operated calcium channels blocking NMDA-mediated ion flux and ameliorating the dangerous effects of pathologically elevated glutamate levels that lead to neuronal dysfunction.8”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Matsunaga S Kishi T Iwata N Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS ONE. 2015; 10:e0123289. PMC4393306 25860130

      Not checked in the free run.

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    Premisecitation

    Further decline occurs after acetylcholinesterase inhibitor treatment, but even temporary discontinuation results in rapid decline and is associated with greater risk of nursing home placement.

    “Further decline occurs, but even temporary discontinuation of these drugs results in rapid decline and is associated with greater risk of nursing home placement.16”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Howard R McShane R Lindesay J, et al Nursing home placement in the donepezil and memantine in moderate to severe Alzheimer’s disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol. 2015; 14: 1171- 1181. 26515660

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    Premisecitation

    Memantine is a noncompetitive low-affinity NMDA-receptor open-channel blocker and affects glutamatergic transmission.

    “Memantine is a noncompetitive low-affinity NMDA-receptor open-channel blocker and affects glutamatergic transmission.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Donepezil and rivastigmine have been approved by FDA for mild, moderate, and severe Alzheimer disease, whereas galantamine is approved for mild and moderate Alzheimer disease.

    “Donepezil and rivastigmine have been approved by FDA for mild, moderate, and severe AD, whereas galantamine for mild and moderate AD.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Rountree SD Atri A Lopez OL Doody RS Effectiveness of antidementia drugs in delaying Alzheimer disease progression. Alzheimers Dement. 2013; 9: 338- 345. 23102979 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Acetylcholinesterase inhibitors enhance central cholinergic neurotransmission and tend to mitigate decline in cognition at least during the first year of treatment.

    “Thus, AChEIs enhance central cholinergic neurotransmission and finally tend to mitigate decline in cognition at least during the first year of treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although in the amyloid hypothesis tau hyperphosphorylation was thought to be downstream of Aβ deposition, it is equally probable that tau and Aβ act in parallel pathways causing Alzheimer disease and enhancing each other's toxic effects.

    “Although in the amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects.3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Scheltens P Blennow K Breteler MMB, et al Alzheimer’s disease. Lancet. 2016; 388: 505- 517. 26921134 source

      Not checked in the free run.

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

    Premisecitation

    According to the amyloid hypothesis, Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of Alzheimer disease.

    “According to the “amyloid hypothesis” Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

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    Premisecitation

    Pharmacokinetic characteristics differ among acetylcholinesterase inhibitors: donepezil and galantamine are primarily eliminated by hepatic metabolism, whereas rivastigmine is eliminated by liver and intestine metabolism.

    “Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and intestine metabolism.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Atri A Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019; 39: 227- 240. 30925615 source

      Not checked in the free run.

    • cites [17] Farlow M Anand R Messina J Hartman R Jr Veach J A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000; 44: 236- 241. 11096224

      Not checked in the free run.

    • cites [18] Rountree SD Atri A Lopez OL Doody RS Effectiveness of antidementia drugs in delaying Alzheimer disease progression. Alzheimers Dement. 2013; 9: 338- 345. 23102979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alzheimer disease could be prevented or effectively treated by decreasing production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing toxic aggregate or misfolded forms; or a combination of these modalities.

    “From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Hampel H Mesulam MM Cuello AC, et al The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018; 141: 1917- 1933. 29850777 PMC6022632 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetylcholinesterase inhibitors increase the availability of acetylcholine at synapses and have been proven clinically useful in delaying cognitive decline in Alzheimer disease.

    “The AChEIs increase the availability of acetylcholine at synapses and have been proven clinically useful in delaying the cognitive decline in AD.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Hampel H Mesulam MM Cuello AC, et al The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018; 141: 1917- 1933. 29850777 PMC6022632 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Donepezil and galantamine selectively and reversibly inhibit acetylcholinesterase, whereas rivastigmine is a pseudo-irreversible inhibitor of acetylcholinesterase and butyrylcholinesterase.

    “Donepezil and galantamine inhibit selectively and reversibly the acetylcholinesterase, whereas rivastigmine is a “pseudo-irreversible” inhibitor of acetylcholinesterase and butyrylcholinesterase.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Atri A Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019; 39: 227- 240. 30925615 source

      Not checked in the free run.

    • cites [17] Farlow M Anand R Messina J Hartman R Jr Veach J A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000; 44: 236- 241. 11096224

      Not checked in the free run.

    • cites [18] Rountree SD Atri A Lopez OL Doody RS Effectiveness of antidementia drugs in delaying Alzheimer disease progression. Alzheimers Dement. 2013; 9: 338- 345. 23102979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetylcholinesterase inhibitors may trigger bradycardia and increase the risk of syncope.

    “The AChEIs may also trigger bradycardia and increase the risk of syncope.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Farlow M Anand R Messina J Hartman R Jr Veach J A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer’s disease. Eur Neurol. 2000; 44: 236- 241. 11096224

      Not checked in the free run.

    • cites [18] Rountree SD Atri A Lopez OL Doody RS Effectiveness of antidementia drugs in delaying Alzheimer disease progression. Alzheimers Dement. 2013; 9: 338- 345. 23102979 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most popular and broadly accepted explanations for multiple failures of clinical trials of disease-modifying treatments for Alzheimer disease include too late starting of therapies, inappropriate drug doses, wrong main target, and mainly inadequate understanding of Alzheimer disease pathophysiology.

    “The most popular and broadly accepted explanations for the multiple failures of clinical trials of DMT agents for AD include the too late starting of therapies in disease development, the inappropriate drug doses, the wrong main target of the treatment, and mainly an inadequate understanding of the pathophysiology of AD.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Gauthier S Albert M Fox N, et al Why has therapy development for dementia failed in the last two decades. Alzheimers Dement. 2016; 12: 60- 64. 26710325

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

    Premisecitation

    Disease-modifying treatment agents were separated into small molecules or biologics (monoclonal antibodies and other immunotherapies).

    “The DMT agents were further separated into small molecules or biologics (monoclonal antibodies [mAbs] and other immunotherapies).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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

    Premisecitation

    Disease-modifying treatment agents were classified according to potential mechanism of action as amyloid targeting, tau-related targeting, and other mechanisms such as anti-inflammatory or metabolic protection, neuroprotection, and growth factor support.

    “The DMT agents were also classified according to their potential MOA as amyloid targeting, as tau-related targeting, and as having other MOA such as anti-inflammatory or metabolic protection, neuroprotection, and growth factor support.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

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    Premisecitation

    Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or behavioral and psychological symptoms of dementia elimination.

    “Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or BPSD elimination.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Atri A Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019; 39: 227- 240. 30925615 source

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    Premisecitation

    Use of clinical trial simulators, Bayesian statistics, and modifiable trial designs is strongly suggested.

    “In addition, the use of clinical trial simulators, Bayesian statistics, and modifiable trial designs is strongly suggested.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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    Premisecitation

    Longer trial durations increase the probability of detecting a significant effect but at the same time increase costs tremendously.

    “Given the fact that longer trial durations increase the probability of detecting a significant effect but at the same time increase tremendously the costs, the proposed solution seems to be the use of clinical trial simulators.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Anderson RM Hadjichrysanthou C Evans S Wong MM Why do so many clinical trials of therapies for Alzheimer’s disease fail? Lancet. 2017; 390: 2327- 2329. 29185425 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A novel approach suggests that selected trials' clinical endpoint may be extremely premature, and variability in diagnostic markers and end points may result in inaccurate diagnosis of patients' disease state and is a source of errors.

    “A novel approach to the problem seems more technical and mathematical than biological and suggests that the selected trials’ clinical endpoint may be extremely premature, and additionally, the variability in diagnostic markers and end points may result in inaccurate diagnosis of patients’ disease state and is finally a definite source of errors.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Anderson RM Hadjichrysanthou C Evans S Wong MM Why do so many clinical trials of therapies for Alzheimer’s disease fail? Lancet. 2017; 390: 2327- 2329. 29185425 source

      Not checked in the free run.

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    Premisecitation

    Clinical trial simulators can help perfect study design, augment the probability of success of estimated new drugs, or save time and resources by indicating earlier the forthcoming failure of inappropriate therapy.

    “They can also help in the perfecting of the design of the study; hence, they may augment the probability of success of estimated new drugs or save invaluable time and resources, by indicating earlier the forthcoming failure of any inappropriate therapy.37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hadjichrysanthou C Ower AK de Wolf F Anderson RM The development of a stochastic mathematical model of Alzheimer’s disease to help improve the design of clinical trials of potential treatments. PLoS ONE. 2018; 13:e0190615. PMC5788351 29377891

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    Premisecitation

    The crucial step in Alzheimer disease pathogenesis is the production of amyloid Aβ, which forms senile plaques (insoluble and proteolysis-resistant fibrils).

    “The crucial step in AD pathogenesis is the production of amyloid (Aβ), which forms SPs (insoluble and proteolysis-resistant fibrils).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

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

    Premisecitation

    Selective serotonin reuptake inhibitors are preferred for treating depression and anxiety in behavioral and psychological symptoms of dementia.

    “Selective serotonin reuptake inhibitors are preferred for treating depression and anxiety.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Bessey LJ Walaszek A Management of behavioral and psychological symptoms of dementia. Curr Psychiatry Rep. 2019; 21: 66. 31264056

      Not checked in the free run.

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    Premisecitation

    The tested agents are classified as disease-modifying treatments (73%), symptomatic cognitive enhancers (13%), and symptomatic for treatment of behavioral and psychological symptoms of dementia (11%).

    “The tested agents are classified as DMTs (73%), symptomatic cognitive enhancers (13%), and symptomatic for the treatment of BPSDs (11%).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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    Premisecitation

    APP cleavage by α-secretase leads to the nonamyloidogenic pathway, whereas APP cleavage by β-secretase (BACE1) leads to the amyloidogenic pathway.

    “The APP cleavage by α-secretase leads to nonamyloidogenic pathway, whereas APP cleavage by β-secretase (BACE1) leads to amyloidogenic pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

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    Premisecitation

    Clinical trial simulators are constructed with mathematical, computational, and statistical tools and can predict the likelihood that a strategy and clinical end point selection of a given trial are proper before trial initiation.

    “These simulators are constructed with mathematical, computational, and statistical tools and can predict the likelihood that a strategy and clinical end point selection of a given trial are proper or not, before the initiation of the trial.36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Romero K Ito K Rogers JA, et al The future is now: model-based clinical trial design for Alzheimer’s disease. Clin Pharmacol Ther. 2015; 97: 210- 214. 25669145 PMC6463482

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    Premisecitation

    No new drug has been approved by FDA for Alzheimer disease since 2003 and there are no approved disease-modifying treatments for Alzheimer disease.

    “No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials.22,28”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Hukins D Macleod U Boland JW Identifying potentially inappropriate prescribing in older people with dementia: a systematic review. Eur J Clin Pharmacol. 2019; 75: 467- 481. 30610274

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    • cites [28] Anderson RM Hadjichrysanthou C Evans S Wong MM Why do so many clinical trials of therapies for Alzheimer’s disease fail? Lancet. 2017; 390: 2327- 2329. 29185425 source

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    Premisecitation

    The National Institute on Aging and the Alzheimer's Association proposed a new framework for research that requires application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in Alzheimer disease stages, and can assist clinical trials design.

    “The National Institute on Aging and the Alzheimer’s Association (NIA-AA) proposed a new framework for research,39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Jack CR Jr Bennett DA Blennow K, et al NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018; 14: 535- 562. 29653606 PMC5958625 source

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    Premisecitation

    Current FDA guidance for Alzheimer disease clinical trials includes use of fluid or neuroradiological biomarkers in disease staging for preclinical and prodromal Alzheimer disease trials and of a single primary outcome in prodromal Alzheimer disease trials.

    “Consequently, current guidance provided by the FDA for AD clinical trials further includes use of fluid or neuroradiological biomarkers in disease staging for preclinical and prodromal AD trials and of a single primary outcome in prodromal AD trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The last annual review of the drug development pipeline for Alzheimer disease examined clinicaltrials.gov in February 2019 (132 agents in 156 trials) and reported 28 drugs in 42 phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials.

    “The last annual review of the drug development pipeline for AD examined clinicaltrials.gov in February, 2019 (132 agents in 156 trials) and provides information and conclusions available at that time: 28 drugs in 42 clinical trials in phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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    Premisecitation

    Combination of memantine and an acetylcholinesterase inhibitor benefits patients with usually additive effects, without any increase in adverse effects.

    “Their combination benefits patients with usually additive effects, without any increase in adverse effects.14,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Na R Yang JH Yeom Y, et al A systematic review and meta-analysis of nonpharmacological interventions for moderate to severe dementia. Psychiatry Investig. 2019; 16: 325- 335. PMC6539264 31132836

      Not checked in the free run.

    • cites [15] Kishita N Backhouse T Mioshi E Nonpharmacological interventions to improve depression, anxiety, and quality of life (QoL) in people with dementia: an overview of systematic reviews. J Geriatr Psychiatry Neurol. 2019; 33: 28- 41. 31203712 source

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    Premisecitation

    Two BACE inhibitors are still elaborated: elenbecestat (E2609) in phase 2 and umibecestat (CNP520) in phase 3.

    “Two BACE inhibitors are still elaborated: elenbecestat (E2609) in phase 2 and umibecestat (CNP520) in phase 3.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness and safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).

    “The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms).10,32-34”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [10] Atri A Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019; 39: 227- 240. 30925615 source

      Not checked in the free run.

    • cites [32] Burki T Alzheimer’s disease research: the future of BACE inhibitors. Lancet. 2018; 391: 2486. 29976459 source

      Not checked in the free run.

    • cites [33] Egan MF Kost J Voss T, et al Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019; 380: 1408- 1420. 30970186 PMC6776078 source

      Not checked in the free run.

    • cites [34] Henley D Raghavan N Sperling R Aisen P Raman R Romano G Preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease. N Engl J Med. 2019; 380: 1483- 1485. 30970197 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APH-1105 is delivered intranasally and is assessed in mild to moderate Alzheimer disease.

    “APH-1105 is delivered intranasally and is assessed in mild to moderate AD.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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

    Premisecitation

    Etazolate is currently evaluated in animal studies for its preventive effect in post-traumatic stress disorder.

    “Etazolate is currently evaluated in animal studies for its preventive effect in post-traumatic stress disorder.49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Alzoubi KH Al Subeh ZY Khabour OF Molecular targets for the interactive effect of etazolate during post-traumatic stress disorder: role of oxidative stress, BDNF and histones. Behav Brain Res. 2019; 369:111930. 31047921

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ42 is the most aggregation-prone form and has the tendency to cluster into oligomers.

    “Aβ42 is the most aggregation-prone form and has the tendency to cluster into oligomers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Etazolate (EHT0202) stimulates the nonamyloidogenic α-secretase pathway acting as a selective modulator of GABA receptors.

    “Etazolate (EHT0202) stimulates the nonamyloidogenic α-secretase pathway acting as a selective modulator of GABA receptors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Vellas B Sol O Snyder PJ, et al EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011; 8: 203- 212. 21222604 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compound 18 mainly prevents aggregation of Aβ42 and can also dissolve oligomerics to a limited extent; it is resilient in proteolytic decomposition.

    “The KLVFF compound that mainly prevents the aggregation of Aβ42 and can also dissolve the oligomerics to a limited extend is the final compound 18, which is resilient in proteolytic decomposition.51”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Stark T Lieblein T Pohland M, et al Peptidomimetics that inhibit and partially reverse the aggregation of Aβ1-42. Biochemistry. 2017; 56: 4840- 4849. 28841311 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase 2 clinical trial in patients with Alzheimer disease did not provide evidence to support a clinical benefit of ELND005, while severe toxicity issues (infections) forced cessation of the study.

    “A phase 2 clinical trial in patients with AD did not provide evidence to support a clinical benefit of ELND005 while severe toxicity issues (infections) forced the cessation of the study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Salloway S Sperling R Keren R, et al; ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011; 77: 1253- 1262. 21917766 PMC3179648 source

      Not checked in the free run.

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

    Premisecitation

    Aβ38 is soluble and present in the vasculature of patients with sporadic and familial Alzheimer disease.

    “Aβ38 is soluble, present in the vasculature of patients with sporadic and familial AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat was associated with worsening of activities in daily living and increased rates of infections and skin cancer, avagacestat was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer), and tarenflurbil showed low brain penetration.

    “This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat29 was associated with worsening of activities in daily leaving and increased rates of infections and skin cancer, avagacestat41 was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration.42”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Doody RS Raman R Farlow M, et al A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013; 369: 341- 350. 23883379 source

      Not checked in the free run.

    • cites [41] Coric V Salloway S van Dyck CH, et al Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015; 72: 1324- 1333. 26414022 source

      Not checked in the free run.

    • cites [42] Muntimadugu E Dhommati R Jain A Challa VG Shaheen M Khan W Intranasal delivery of nanoparticle encapsulated tarenflurbil: a potential brain targeting strategy for Alzheimer’s disease. Eur J Pharm Sci. 2016; 92: 224- 234. 27185298

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KLVFF is a peptide sequence that resembles the hydrophobic central part of Aβ and gradually replaces natural polypeptides.

    “KLVFF is a peptide sequence that resembles the hydrophobic central part of the Aβ and gradually replaces natural polypeptides.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Stark T Lieblein T Pohland M, et al Peptidomimetics that inhibit and partially reverse the aggregation of Aβ1-42. Biochemistry. 2017; 56: 4840- 4849. 28841311 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Major sites of γ-secretase cleavage usually occur at positions 40 and 42 of Aβ, so Aβ40 and Aβ42 oligomers are the main products of sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of greater plentifulness of BACE1.

    “Major sites of γ-secretase cleavage usually occur in positions 40 and 42 of Aβ, thus Aβ40 and Aβ42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

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

    Premisecitation

    Aβ40 usually constitutes more than 50% of total detected Aβ.

    “Aβ40 usually constitutes more than 50% of total detected Aβ.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Restricted knowledge assumes that α-secretase activation is promoted through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through γ-aminobutyric acid (GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as selective GABA receptor modulators are suggested as potential therapeutic drugs for Alzheimer disease.

    “Restricted, nowadays, knowledge assumes that α-secretase activation is promoted through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through γ-aminobutyric acid (GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as selective GABA receptor modulators are suggested as potential therapeutic drugs for AD.47,48”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Cho WH Park JC Kim DH, et al ID1201, the ethanolic extract of the fruit of Melia toosendan ameliorates impairments in spatial learning and reduces levels of amyloid beta in 5XFAD mice. Neurosci Lett. 2014; 583: 170- 175. 25281546 source

      Not checked in the free run.

    • cites [48] Vellas B Sol O Snyder PJ, et al EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011; 8: 203- 212. 21222604 source

      Not checked in the free run.

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

    Premisecitation

    Aβ40 is somewhat aggregation-prone and is mostly found in the cerebral vasculature as a main component of cerebral amyloid angiopathy.

    “Aβ40 is somewhat aggregation-prone and it is mostly found in the cerebral vasculature as a main component of “cerebral amyloid angiopathy.””
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All BACE inhibitor agents showed significant and dose-dependent reduction of cerebrospinal fluid Aβ42, but without cognitive or functional benefit, while many were poorly tolerated and some failed in subjects with prodromal Alzheimer disease.

    “All agents showed significant and dose-dependent result of reducing CSF Aβ42, but without cognitive or functional benefit while many of them were poorly tolerated and some of them failed in subjects with prodromal AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Panza F Lozupone M Solfrizzi V, et al BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev Neurother. 2018; 18: 847- 857. 30277096

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    γ-secretase acts on many other substances and cleaves different transmembrane proteins, including Notch receptor 1, which is essential for control of normal cell differentiation and communication.

    “Unluckily, concerning γ-secretase, in addition to APP, this particular enzyme acts on many other substances and cleaves different transmembrane proteins. Notch receptor 1, which is essential for control of normal cell differentiation and communication, is among them.5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Yiannopoulou KG Papageorgiou SG Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord. 2013; 6: 19- 33. 23277790 PMC3526946 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ID1201 is a fruit extract of melia toosendan and induces α-secretase activation; it is evaluated in mild Alzheimer disease.

    “ID1201 is a fruit extract of melia toosendan and also induces α-secretase activation. It is evaluated in mild AD.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Cho WH Park JC Kim DH, et al ID1201, the ethanolic extract of the fruit of Melia toosendan ameliorates impairments in spatial learning and reduces levels of amyloid beta in 5XFAD mice. Neurosci Lett. 2014; 583: 170- 175. 25281546 source

      Not checked in the free run.

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

    Interpretationreasoning

    It is possible that effective Alzheimer disease immunotherapies must be able to simultaneously target both ptau and Aβ pathologies.

    “Consequently, it is possible that effective AD immunotherapies must be able to simultaneously target both ptau and Aβ pathologies.56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Wisniewski T Goñi F Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015; 85: 1162- 1176. 25789753 PMC4366618 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Aβ-targeted strategies seem promising if used very early in the progression of Alzheimer disease, before the presence of any symptoms; thus, they are developed in current trials in preclinical Alzheimer disease.

    “Overall, Aβ-targeted strategies seem promising if used very early in the progression of the disease, before the presence of any symptoms; thus, they are developed in current trials in preclinical AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CAD106 is an active Aβ immunotherapeutic agent studied in preclinical Alzheimer disease under the Alzheimer prevention initiative generation program, which comprises 2 phase 3 studies evaluating safety and efficacy of CAD106 and umibecestat in asymptomatic individuals at risk of developing Alzheimer disease.

    “CAD106 is an active Aβ immunotherapeutic agent, is studied in preclinical AD under the umbrella of the Alzheimer prevention initiative generation program, which comprises 2 phase 3 studies that evaluate simultaneously the safety and efficacy of CAD106 and umibecestat in asymptomatic individuals at risk of developing AD (60-75 years of age, APOE4 homozygotes, or APOE4 heterozygotes with elevated Am”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Lopez Lopez C Tariot PN Caputo A, et al The Alzheimer’s Prevention Initiative Generation Program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement; 5: 216- 227. PMC6562315 31211217 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PBT2, a metal protein-attenuating compound, has recently progressed in phase 2 Alzheimer disease treatment trials, as it demonstrated promising efficacy data in preclinical studies.

    “A metal protein–attenuating compound, PBT2, has recently progressed in phase 2 AD treatment trials, as it demonstrated promising efficacy data in preclinical studies.54”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Krishnan HS Bernard-Gauthier V Placzek MS Metal protein-attenuating compound for PET neuroimaging: synthesis and preclinical evaluation of [11C]PBT2. Mol Pharm. 2018; 15: 695- 702. 29298483

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antigen-presenting cells present immunogens to B cells; use of Aβ or ptau peptides produces antibodies to Aβ or ptau epitopes, respectively; use of pBri produces antibodies to both Aβ and ptau epitopes.

    “Antigen-presenting cells present the immunogens to B cells. Use of Ab or ptau peptides will produce antibodies to Ab or ptau epitopes, respectively. Use of pBri will produce antibodies to both Aβ and ptau epitopes.56”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Wisniewski T Goñi F Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015; 85: 1162- 1176. 25789753 PMC4366618 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ABvac40 is evaluated in a phase 2 study as the first active vaccine against the C-terminal end of Aβ40.

    “ABvac40 is evaluated in a phase 2 study, as the first active vaccine against the C-terminal end of Aβ40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Lopez Lopez C Tariot PN Caputo A, et al The Alzheimer’s Prevention Initiative Generation Program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement. 2019; 12: 216- 227. PMC6562315 31211217 source

      Not checked in the free run.

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

    Premisecitation

    ABri is a rare hereditary amyloidosis associated with a mutation that results in production of a highly amyloidogenic protein with a unique carboxyl terminus that has no homology to any other human protein.

    “ABri is a rare hereditary amyloidosis associated with a mutation that results in the production of a highly amyloidogenic protein with a unique carboxyl terminus that has no homology to any other human protein.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Goñi F Herline K Peyser D, et al Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models. J Neuroinflammation. 2013; 10: 150. 24330773 PMC3878790

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 3-month phase 2 study, PBT2 succeeded in a 13% reduction of cerebrospinal fluid Aβ and an executive function improvement in a dose-related pattern in patients with early Alzheimer disease.

    “In a 3-month phase 2 study, PBT2 succeeded in a 13% reduction of CSF Aβ and an executive function improvement in a dose-related pattern in patients with early AD.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Villemagne VL Rowe CC Barnham KJ, et al A randomized, exploratory molecular imaging study targeting amyloid β with a novel 8-OH quinoline in Alzheimer’s disease: the PBT2-204 IMAGINE study. Alzheimers Dement. 2017; 3: 622- 635. PMC5702880 29201996

      Not checked in the free run.

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

    Premisecitation

    GV1001 peptide (tertomotide) was previously studied as a vaccine against various cancers, whereas now it is evaluated in a phase 2 study for Alzheimer disease.

    “GV1001 peptide (tertomotide) was previously studied as a vaccine against various cancers, whereas now it is evaluated in a phase 2 study for AD.60”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Lacosta AM Pascual-Lucas M Pesini P, et al Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebocontrolled, phase I trial. Alzheimers Res Ther. 2018; 10: 12. 29378651 PMC5789644 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunotherapeutic approaches have dominated in the past 15 years with negative results until now.

    “Immunotherapeutic approaches have dominated in the past 15 years with negative results until now.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Wisniewski T Goñi F Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015; 85: 1162- 1176. 25789753 PMC4366618 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UB-311, a synthetic peptide used as Aβ vaccine, has been advanced into an ongoing phase 2 study in patients with mild and moderate Alzheimer disease; in phase 1, it induced a 100% responder rate, usual adverse effects were swelling at the injection site and agitation, and a slower cognitive decline rate was observed in patients with mild Alzheimer disease.

    “UB-311, a synthetic peptide used as Aβ vaccine, has been advanced into an ongoing phase 2 study in patients with mild and moderate AD. In phase 1, it induced a 100% responder rate in patients with AD. The usual adverse effects were swelling in the injection site and agitation. A slower cognitive decline rate was observed in patients with mild AD.62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Hull M Sadowsky C Arai H, et al Long-term extensions of randomized vaccination trials of ACC-001 and QS-21 in mild to moderate Alzheimer’s disease. Curr Alzheimer Res. 2017; 14: 696- 708. 28124589 PMC5543567 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Monoclonal antibodies to Aβ, ptau, or β sheet epitopes are systemically infused for blood-brain barrier penetration; as antibodies cross the blood-brain barrier, they clear, degrade, disaggregate, or neutralize their targets.

    “Monoclonal Abs to Ab, ptau, or b sheet epitopes are systemically and adequately for BBB penetration infused. As antibodies cross the BBB, they act to clear, degrade, or alternatively disaggregate or neutralize their targets.56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Wisniewski T Goñi F Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015; 85: 1162- 1176. 25789753 PMC4366618 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The design of monoclonal antibody studies became more specific and targeted: amyloid-related imaging abnormalities were associated with dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required.

    “Furthermore, the design of the studies became more specific and targeted: the characteristics of amyloid-related imaging abnormalities were associated with the dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Atri A Current and future treatments in Alzheimer’s disease. Semin Neurol. 2019; 39: 227- 240. 30925615 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The pBri peptide corresponds to this terminus and induces an immune response that recognizes Aβ and ptau.

    “The pBri peptide corresponds to this terminus and induces an immune response that recognizes Aβ and ptau.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Goñi F Herline K Peyser D, et al Immunomodulation targeting of both Aβ and tau pathological conformers ameliorates Alzheimer’s disease pathology in TgSwDI and 3xTg mouse models. J Neuroinflammation. 2013; 10: 150. 24330773 PMC3878790

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACC-001 (vanutide cridificar), an Aβ vaccine, was studied in phase 2a extension studies in subjects with mild to moderate Alzheimer disease; administered with QS-21 adjuvant, long-term therapy was very well tolerated and produced the highest anti-Aβ IgG titers compared with other regimens.

    “ACC-001 (vanutide cridificar), an Aβ vaccine, was studied in phase 2a extension studies in subjects with mild to moderate AD. It was administered with QS-21 adjuvant. Long-term therapy with this combination was very well tolerated and produced the highest anti-Aβ IgG titers compared with other regimens.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Kim H Seo EH Lee SH Kim BJ The telomerase-derived anticancer peptide vaccine GV1001 as an extracellular heat shock protein-mediated cell-penetrating peptide. Int J Mol Sci. 2016; 17: E2054. PMC5187854 27941629

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Strict inclusion criteria were applied in monoclonal antibody trials, such as biomarker proof of amyloid positivity and enrollment of individuals with preclinical stages of the disease.

    “Strict inclusion criteria were applied, such as biomarker proof of “amyloid positivity” and enrollment of individuals with preclinical stages of the disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a phase 1 study with patients with mild to moderate Alzheimer disease aged 50 to 85 years, neither incident vasogenic edema nor microhemorrhages were identified, and specific anti-Aβ40 antibodies were developed in 92% of individuals receiving ABvac40 injections.

    “A phase 1 study was conducted with patients with mild to moderate AD aged 50 to 85 years. Neither incident vasogenic edema nor microhemorrhages were identified. Specific anti-Aβ40 antibodies were developed in the 92% of the individuals receiving injections of ABvac40.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Lopez Lopez C Tariot PN Caputo A, et al The Alzheimer’s Prevention Initiative Generation Program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement. 2019; 12: 216- 227. PMC6562315 31211217 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many ongoing mAbs trials are in phase 3, including crenezumab, gantenerumab, and solanezumab in studies for preclinical or at-risk populations.

    “and crenezumab,70 gantenerumab, and solanezumab71 in studies for preclinical or at-risk populations”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [70] Logovinsky V Satlin A Lai R, et al Safety and tolerability of BAN2401–a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016; 8: 14. 27048170 PMC4822297

      Not checked in the free run.

    • cites [68] Sevigny J Chiao P Bussière T, et al The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016; 537: 50- 56. 27582220 source

      Not checked in the free run.

    • cites [71] Yang T Dang Y Ostaszewski B, et al Target engagement in an Alzheimer trial: crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann Neurol. 2019; 86: 215- 224. 31168802 PMC6771589 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eleven symptomatic agents are studied in phase 3: 3 cognitive intensifiers and 8 acting on BPSD.

    “Eleven of them are studied in phase 3: 3 cognitive intensifiers and 8 acting on BPSD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Twenty symptomatic agents are in phase 2: 14 cognitive intensifiers and 6 acting on BPSD.

    “Twenty symptomatic agents are in phase 2: 14 cognitive intensifiers and 6 acting on BPSD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only 1 agent with tau-related mechanism is evaluated in phase 2/3, 10 agents that target tau as one of their mechanisms are evaluated in phase 2, and 5 more agents with tau-related mechanism are assessed in phase 1 studies.

    “Only 1 agent with tau-related mechanism is evaluated in phase 2/3, whereas 10 agents that target tau as one of their mechanisms are evaluated in phase 2, and 5 more agents with tau-related mechanism are assessed in phase 1 studies.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPT088 reduced Aβ and ptau aggregates and improved cognition in aged Tg2576 mice.

    “NPT088 reduced Aβ and ptau aggregates and improved cognition in aged Tg2576 mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Levenson JM Schroeter S Carroll JC, et al NPT088 reduces both amyloid-β and tau pathologies in transgenic mice. Alzheimers Dement. 2016; 2: 141- 155. PMC5651359 29067301

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients treated with ANAVEX 2-73 had high levels of 2 gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living.

    “patients treated with ANAVEX 2-73 had high levels of 2 gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Parmentier F Etcheto A Missling CU, et al Exploring Gut Microbiota as a Source of Potential Biomarkers: Initial Results from the ANAVEX®2-73 Alzheimer’s Disease Clinical Study [O4-02-04]. AAIC; 2019 http://www.arianapharma.com/wp-content/uploads/2019/07/Anavex-Microbiota-Presentation-AAIC-July-2019-FINAL-1.pdf.

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    There are 2 cognitive intensifiers being studied in phase 1.

    “There are also 2 cognitive intensifiers being studied in phase 1.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A monotherapy trial with methylene blue on mild and moderate AD demonstrated some clinical benefit in moderate, but not mild AD.

    “A monotherapy trial with MB on mild and moderate AD (NCT00515333) has demonstrated some clinical benefit in moderate, but not mild AD.82”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Wischik CM Staff RT Wischik DJ, et al Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer’s disease. J Alzheimers Dis. 2015; 44: 705- 720. 25550228 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy on clinical stability or delay of cognitive or functional decline in participants with mild and moderate AD.

    “the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD.74”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Schwarz AJ Sundell KL Charil A, et al Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer’s disease. Alzheimers Dement. 2019; 5: 328- 337. PMC6675941 31388559

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNF-α signaling has been proved to exacerbate both Aβ aggregation and tau phosphorylation in vivo.

    “TNF-α signaling has been proved to exacerbate both Aβ aggregation and tau phosphorylation in vivo,90”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Alam Q Alam MZ Mushtaq G, et al Inflammatory process in Alzheimer’s and Parkinson’s diseases: central role of cytokines. Curr Pharm Des. 2016; 22: 541- 548. 26601965

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AGB101 (low-dose extended-release levetiracetam) is an SV2A modulator assessed in a phase 3 clinical trial as a repurposed agent for MCI due to AD.

    “AGB101 (low-dose extended-release levetiracetam) is an SV2A modulator that is assessed in a phase 3 clinical trial as a repurposed agent (approved for use in another indication, not epilepsy but MCI due to AD).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overall, there are 33 symptomatic agents in current trials: 19 aim to improve cognition and 14 target BPSD.

    “Overall, there are 33 symptomatic agents in current trials: 19 agents aim to improve cognition and 14 target BPSD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    COR388 targets a periodontal pathogen acting as bacterial protease inhibitor that reduces neuroinflammation and consequently hippocampal degeneration and is currently assessed in a phase 3 clinical trial.

    “COR388 targets a periodontal pathogen acting as bacterial protease inhibitor that reduces neuroinflammation and consequently hippocampal degeneration and is currently assessed in a phase 3 clinical trial (NCT03823404).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NDX-1017 is an hepatocyte growth factor with the role to regenerate neurons, studied in a phase 1 clinical trial.

    “NDX-1017 is an hepatocyte growth factor with the role to regenerate neurons, which is studied in a phase 1 clinical trial (NCT03298672).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BHV4157 (troriluzole) is a glutamate modulator that reduces synaptic levels of glutamate and is assessed in a phase 3 clinical trial.

    “BHV4157 (troriluzole) is a glutamate modulator that reduces synaptic levels of glutamate and is assessed in a phase 3 clinical trial (NCT03605667).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Losartan plus amlodipine plus atorvastatin plus exercise is a combination repurposed agent suggested to succeed significant reduction of vascular risk capable of preserving cognitive function and is assessed in a phase 3 clinical trial.

    “Losartan plus amlodipine plus atorvastatin plus exercise is a combination repurposed agent suggested to succeed significant reduction of the vascular risk capable of preserving cognitive function. It is assessed in a phase 3 clinical trial (NCT02913664).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Masitinib acts on mast cells as a selective tyrosine kinase inhibitor and a modulator of neuroinflammation and is assessed in a phase 3 clinical trial.

    “Masitinib acts on mast cells as a selective tyrosine kinase inhibitor and a modulator of neuroinflammation. It is assessed in a phase 3 clinical trial (NCT01872598).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AstroStem is currently assessed in a phase 2 study, whereas hMSCs treatment is assessed in a phase 1 study.

    “AstroStem is currently assessed in a phase 2 study (NCT03117738), whereas hMSCs (human mesenchymal stem cells) treatment is assessed in a phase 1 study (NCT02600130).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Candesartan, formoterol, and intranasal insulin glulisine are currently studied in phase 2 clinical trials, whereas intranasal insulin aspart is assessed in a phase 1 clinical study.

    “Candesartan, an angiotensin receptor blocker; formoterol, a β2 adrenergic receptor agonist; and intranasal insulin glulisine, which rises brain insulin signaling, are currently studied in phase 2 clinical trials (NCT02646982, NCT02500784, NCT02503501, respectively), whereas intranasal insulin aspart is assessed in a phase 1 clinical study.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Icosapent ethyl is supposed to protect neurons from disease pathology and is assessed in a phase 3 clinical trial.

    “Icosapent ethyl is the eicosapentaenoic acid (EPA) omega-3 fatty acid in a purified form. It is supposed to protect neurons from disease pathology and is assessed in a phase 3 clinical trial (NCT02719327).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are 2 biologics and 24 small molecules with neuroprotection as one of their mechanisms assessed in phase 2 clinical studies and 8 small molecules in phase 1 clinical trials.

    “There are also 2 biologics and 24 small molecules with neuroprotection as one of their mechanisms4 assessed in phase 2 clinical studies and 8 small molecules in phase 1 clinical trials.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

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

    Premisecitation

    Elderberry Juice improves mitochondrial function acting as powerful antioxidant rich in anthocyanins and GRF6019 is a human plasma protein fraction administered with infusions, based on the hypothesis that brain neuroinflammation can be counteracted by young blood parabiosis.

    “Elderberry Juice improves the mitochondrial function acting as powerful antioxidant rich in anthocyanins (NCT02414607) and GRF6019, a human plasma protein fraction administered with infusions, based on the hypothesis that brain neuroinflammation can be counteracted by young blood parabiosis (NCT03520998, NCT03765762).4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cummings J Lee G Ritter A Sabbagh M Zhong K Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 2019; 5: 272- 293. PMC6617248 31334330 source

      Not checked in the free run.

89 of 89

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?

  • Donepezil, galantamine, and rivastigmine are the most frequently prescribed cholinesterase inhibitors.

    “Donepezil, galantamine, and rivastigmine are the cholinesterase inhibitors that are most frequently prescribed [102,103,104,105,106].”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [102]

  • Memantine monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe Alzheimer's disease, improving quality of life, cognition, and behavioral and psychological symptoms.

    “Monotherapy has shown beneficial effects in the short and long term in patients with moderate to severe AD, improving their quality of life, cognition, and behavioral and psychological symptoms of neurodegenerative diseases [33,34]”

    From Multi-Target Mechanisms of Phytochemicals in Alzheimer’s Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation (2022) · cites this paper as [34]

  • In preclinical models, decreasing tau protein levels via ASO strategies and recently by engineered zinc-finger transcription factors was shown to be durable and to reverse tau pathology.

    “In fact, in preclinical models, decreasing tau protein levels via ASO strategies185,186 and recently by engineered zinc-finger transcription factors187 was shown to be durable and to reverse tau pathology.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [186]

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 article has conflicting volume numbers

    Minor

    References 45 and 59 have the same title, page range, PMC ID, and PMID, but list different journal volumes: 5 and 12.

1 of 1

Cites

Flagged first, then by citations

2 of the 96 references couldn’t be matched to a known paper.

Research works printed but not linked: 5

  1. Savolainen-Peltonen H, 2019, BMJ, 364
  2. Lopez Lopez C, 2019, Alzheimers Dement, 12, 216, 10.1016/j.trci.2019.02.005 · DOI · Paper page
  3. Yiannopoulou KG, 2009, Primary Psychiatry, 16, 29
  4. Doody R, 2017, J Prev Alzheimers Dis, 4, 264
  5. U.S. Food and Drug Administration, U.S. Department of Health and Human Services, 2018, Adaptive Designs for Clinical Trials of Drugs and Biologics

Cited by

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Related

Authors
Yiannopoulou, K. G., & Papageorgiou, S. G.
Affiliations
  • Henry Dunant Hospital (GR)
  • National and Kapodistrian University of Athens (GR)
Corresponding author
Yiannopoulou, Konstantina G
ORCID
Venue
Journal of Central Nervous System Disease
Publisher
SAGE Publications
Published
2020-01
Volume
12
Pages
117957352090739
ISSN
1179-5735 (ISSN-L)
DOI
10.1177/1179573520907397
PMC
PMC7050025
OpenAlex
W3007853567
Semantic Scholar
35a37a9e5cb7e502b1d43a326dbbe0efe4d86057
Cited by
966
References
96
Citations by year
2026: 122 · 2025: 171 · 2024: 214 · 2023: 204 · 2022: 136 · 2021: 93 · 2020: 26
FWCI
14.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Central Nervous System Disease (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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, disease-modifying therapy, cholinesterase inhibitors, memantine, amyloid plaques, neurofibrillary tangles, neuroprotection, anti-inflammatory therapy, growth factor therapy, stem cell therapy, biomarkers, precision medicine, clinical trial design

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.

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