Cited by 429Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial

Open access

Gauthier, Serge, Feldman, Howard H, Schneider, Lon S, Wilcock, Gordon K, Frisoni, Giovanni B, Hardlund, Jiri H, Moebius, Hans J, Bentham, Peter, Kook, Karin A, Wischik, Damon J, Schelter, Bjoern O, Davis, Charles S, Staff, Roger T, Bracoud, Luc, Shamsi, Kohkan, Storey, John M D, Harrington, Charles R, Wischik, Claude M·2016·The Lancet

DOI 10.1016/s0140-6736(16)31275-2PMC PMC5164296

Open this paper in CoChat — free account

Abstract

Background Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease.Methods We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11).Findings Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants.Interpretation The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon.Funding TauRx Therapeutics.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(16)31275-2

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

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?

Self-check

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

The self-check needs the paper’s full text.

The Columbia–Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., Currier, G. W., Melvin, G. A., Greenhill, L., Shen, S., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10111704 · Cited by 5,157
World Alzheimer Report 2015 - The Global Impact of Dementia:An analysis of prevalence, incidence, cost and trends
(2015) · HAL · Cited by 2,238
The clinical use of structural MRI in Alzheimer disease
Frisoni, G. B., Fox, N. C., Jack, C. R., Scheltens, P., & Thompson, P. M. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.215 · Cited by 2,113
Self-citation
Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960
Defeating Alzheimer's disease and other dementias: a priority for European science and society
Winblad, B., Amouyel, P., Andrieu, S., Ballard, C., Brayne, C., Brodaty, H., Cedazo-Minguez, A., Dubois, B., Edvardsson, D., Feldman, H., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00062-4 · Cited by 1,676
Self-citation
Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease
Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1312889 · Cited by 1,668
Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme
Inestrosa, N. C., Alvarez, A. R., Pérez, C. A., Moreno, R. D., Vicente, M., Linker, C., Casanueva, O. I., Soto, C. A., & Garrido, J. (1996) · Neuron · doi:10.1016/s0896-6273(00)80108-7 · Cited by 1,117
Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.
Wischik, C. M., Novak, M., Thøgersen, H. C., Edwards, P. C., Runswick, M. J., Jakes, R., Walker, J. E., Milstein, C., Roth, M., & Klug, A. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.12.4506 · Cited by 939
Self-citation
The pathological process underlying Alzheimer’s disease in individuals under thirty
Braak, H., & Del Tredici, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-010-0789-4 · Cited by 812
Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls
Maruyama, M., Shimada, H., Suhara, T., Shinotoh, H., Ji, B., Maeda, J., Zhang, M.-R., Trojanowski, J. Q., Lee, V. M.-Y., Ono, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.037 · Cited by 760

Show all 31 references

Sorted by citations

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
Tau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870
Alzheimer's disease drug development pipeline: 2019
Cummings, J., Lee, G., Ritter, A., Sabbagh, M., & Zhong, K. (2019) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.05.008 · Cited by 762
“A phase 3 trial of this agent failed to show a drug-placebo difference [19], and based on the results, a new phase 2/3 trial (LUCIDITY) was started in 2018 with a lower dose of LMTX as monotherapy.”
Background
Alzheimer’s disease hypothesis and related therapies
Du, X., Wang, X., & Geng, M. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0107-y · Cited by 623
“For Tau aggregation blockers, TRx0237 failed to show treatment benefits in phase III trials [40].”
Background
Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015
Mehta, D. G., Jackson, R., Paul, G., Shi, J., & Sabbagh, M. N. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1323868 · Cited by 626
Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade
Savelieff, M. G., Nam, G., Kang, J., Lee, H. J., Lee, M., & Lim, M. H. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00138 · Cited by 612
Treatment Combinations for Alzheimer’s Disease: Current and Future Pharmacotherapy Options
Cummings, J. L., Tong, G., & Ballard, C. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-180766 · Cited by 588
Alzheimer’s disease: Recent treatment strategies
Vaz, M., & Silvestre, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173554 · Cited by 547
Alzheimer's disease drug development pipeline: 2017
Cummings, J., Lee, G., Mortsdorf, T., Ritter, A., & Zhong, K. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.05.002 · Cited by 549
“Leuco-methylthioninium (LMTM) (or TRx0237) derived from methylene blue and addressing tau aggregation completed its phase III trials in 2016 and failed to meet prespecified outcomes of the trial [22]; however, its open-label extension study is listed as ongoing.”
Background
Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches
Boxer, A. L., Yu, J.-T., Golbe, L. I., Litvan, I., Lang, A. E., & Höglinger, G. U. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30157-6 · Cited by 485
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 483
Tau-targeting therapies for Alzheimer disease: Current status and future directions
Congdon, E. E., Ji, C., Tetlow, A. M., Jiang, Y., & Sigurdsson, E. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00883-2 · Cited by 371
“Several phase III trials of this drug have been initiated in people with mild-to-moderate AD, along with an open-label extension study for individuals who completed the earlier trials 152–155 .”
Background
Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease
Korte, N., Nortley, R., & Attwell, D. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02215-w · Cited by 365
New Insights Into the Pathogenesis of Alzheimer's Disease
Fan, L., Mao, C., Hu, X., Zhang, S., Yang, Z., Hu, Z., Sun, H., Fan, Y., Dong, Y., Yang, J., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2019.01312 · Cited by 362
Tauopathies: new perspectives and challenges
Zhang, Y., Wu, K.-M., Yang, L., Dong, Q., & Yu, J.-T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00533-z · Cited by 323
A walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 299
Tau PET imaging: present and future directions
Saint‐Aubert, L., Lemoine, L., Chiotis, K., Leuzy, A., Rodriguez‐Vieitez, E., & Nordberg, A. K. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0162-3 · Cited by 300
“While few results from such trials are as yet available, a recent phase III study testing the tau protein aggregation inhibitor Methylthioninium reported no benefit from the treatment in patients with mild to moderate AD [123].”
Result
Tau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272
Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies
Chen, Y., Fu, A. K. Y., & Ip, N. Y. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.006 · Cited by 258
18F-MK-6240 PET for early and late detection of neurofibrillary tangles
Pascoal, T. A., Therriault, J., Benedet, A. L., Savard, M., Lussier, F. Z., Chamoun, M., Tissot, C., Qureshi, M. N. I., Kang, M. S., Mathotaarachchi, S. S., et al. (2020) · Brain · doi:10.1093/brain/awaa180 · Cited by 263
“groups is important for clinical diagnosis, population enrichment of clinical trials, and for assessing clinical changes associated with tau pathology (Gauthier et al., 2016; Jack et al., 2016).”
BackgroundSelf-citation
Microglia and Alzheimer’s Disease
Merighi, S., Nigro, M., Travagli, A., & Gessi, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112990 · Cited by 236
“For instance, phase III studies of the tau accumulation blocker TRx0237 [11] revealed its unsuccess.”
Background
Four-repeat tauopathies
Rösler, T. W., Marvian, A. T., Brendel, M., Nykänen, N.-P., Höllerhage, M., Schwarz, S. C., Hopfner, F., Koeglsperger, T., Respondek, G., Schweyer, K., et al. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101644 · Cited by 231
Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial
Wilcock, G. K., Gauthier, S., Frisoni, G. B., Jia, J., Hardlund, J. H., Moebius, H. J., Bentham, P., Kook, K. A., Schelter, B. O., Wischik, D. J., et al. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-170560 · Cited by 219
“The as-randomised analysis of an earlier Phase III trial (TRx237-015) has been reported [16].”
MethodResultInfluentialSelf-citation
Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease
Morris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212
Updates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 241
“By comparing the cognitive abilities and measuring the rate of brain atrophy, researchers found that the LMTX monotherapy led to significant improvements in cognitive performance and a significant reduction in the rate of brain atrophy at doses of 100 mg or 4 mg twice daily [595].”
Result
New Approaches for the Treatment of Alzheimer’s Disease
Fish, P. V., Steadman, D., Bayle, E. D., & Whiting, P. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.11.034 · Cited by 189
Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review
Yu, T.-W., Lane, H., & Lin, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158208 · Cited by 190
“LMTX Disrupts polymerization Mild to moderate AD Phase III Lack of efficacy [48]”
Background
Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks
Peng, Y., Jin, H., Xue, Y.-H., Chen, Q., Yao, S., Du, M., & Liu, S. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1206572 · Cited by 189
“Moreover, two Phase III studies [(NCT01689246)/the European Union Clinical Trials Registry (2012-002866-11), (NCT01689233) and the European Union Clinical Trials Registry (21012-002847- 28)] confirmed that TRx0237 improved the cognition in patients with mild to moderate AD, such as changes in ADAS-Cog and Alzheimer’s…”
BackgroundInfluential
Docosahexaenoic and Arachidonic Acids as Neuroprotective Nutrients throughout the Life Cycle
Sambra, V., Echeverría, F., Valenzuela, A., Chouinard‐Watkins, R., & Valenzuela, R. (2021) · Nutrients · doi:10.3390/nu13030986 · Cited by 166
From Mitochondrial Function to Neuroprotection—an Emerging Role for Methylene Blue
Tucker, D., Lu, Y., & Zhang, Q. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0712-2 · Cited by 162
“Bioavailability also is modulated by oxidation status, as a stabilized version of the reduced form of MB displays markedly increased brain uptake, which has been factored into a recent clinical trial to be discussed in a subsequent section [14,15].”
An Overview on the Clinical Development of Tau-Based Therapeutics
Medina, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041160 · Cited by 156
“Finally, a multinational, randomized, placebo-controlled, double-blind, parallel-group clinical trial intended to demonstrate safety and efficacy after 12-month oral treatment has been very recently completed in 220 patients with behavioral variant frontotemporal dementia (bvFTD) (NCT01626378), although results remain…”
Background
Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice
Ferretti, M. T., Martínková, J., Biskup, E. M., Benke, T., Gialdini, G., Nedelská, Z., Rauen, K., Mantua, V., Religa, D., Hort, J., et al. (2020) · European Journal of Neurology · doi:10.1111/ene.14174 · Cited by 152
Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer’s disease from a ferroptosis perspective
Derry, P. J., Hegde, M. L., Jackson, G. R., Kayed, R., Tour, J. M., Tsai, A.-L., & Kent, T. A. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101716 · Cited by 146
“, 2014) was carried through a Phase III trial but failed to meet its endpoints of reducing the rate of cognitive decline (Gauthier et al., 2016).”
Background
Tau strains shape disease
Vaquer‐Alicea, J., Diamond, M. I., & Joachimiak, Ł. A. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02301-7 · Cited by 139
The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes
Buchholz, S., & Zempel, H. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13784 · Cited by 154
Role of natural products for the treatment of Alzheimer’s disease
Noori, T., Dehpour, A. R., Sureda, A., Sobarzo-Sanchez, E., & Shirooie, S. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.173974 · Cited by 141
Research Progress in the Pathogenesis of Alzheimer's Disease
Chen, Y. (2018) · Chinese Medical Journal · doi:10.4103/0366-6999.235112 · Cited by 141
“[18] Research[19] challenges the neurotoxic effects of tau phosphorylation in AD nosogenesis and the research found that at least in the early stage of AD, phosphorylation of characteristic sites in tau protein was able to inhibit the toxicity of Aβ, being that tau phosphorylation‑mediated by p38MAPK can antagonize th…”
BackgroundInfluential
Drug development for alzheimer’s disease: Microglia induced neuroinflammation as a target
Dong, Y., Li, X., Cheng, J., & Hou, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030558 · Cited by 136
“However, in recent trials, LMTM demonstrated no significant beneficial effect in the add-on therapy of mild to moderate AD (NCT01689246) [191].”
Background
New Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 136
Tau Oligomers Neurotoxicity
Niewiadomska, G., Niewiadomski, W., Steczkowska, M., & Gąsiorowska, A. (2021) · Life · doi:10.3390/life11010028 · Cited by 138
What is brain health and why is it important?
Wang, Y., Pan, Y., & Li, H. (2020) · BMJ · doi:10.1136/bmj.m3683 · Cited by 140
The prion model for progression and diversity of neurodegenerative diseases
Stopschinski, B. E., & Diamond, M. I. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30037-6 · Cited by 133
Development of disease-modifying drugs for frontotemporal dementia spectrum disorders
Panza, F., Lozupone, M., Seripa, D., Daniele, A., Watling, M., Giannelli, G., & Imbimbo, B. P. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0330-x · Cited by 122
Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau
Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00840-3 · Cited by 118
Degradation and Transmission of Tau by Autophagic-Endolysosomal Networks and Potential Therapeutic Targets for Tauopathy
Jiang, S., & Bhaskar, K. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.586731 · Cited by 119
“Apart from the degradation of intracellular components, autophagy has also been shown to regulate the ER- and Golgiindependent unconventional secretion of several leaderless proteins, like cystic fibrosis transmembrane conductance regulator (CFTR) (Gee et al., 2011), IL-1β (Dupont et al., 2011), and High Mobility Grou…”
Background
Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies
Sarker, M. R., & Franks, S. F. (2018) · GeroScience · doi:10.1007/s11357-018-0017-z · Cited by 110
Natural Products in Alzheimer’s Disease Therapy: Would Old Therapeutic Approaches Fix the Broken Promise of Modern Medicines?
Habtemariam, S. (2019) · Molecules · doi:10.3390/molecules24081519 · Cited by 115
“As with the Aβ approach, the lack of efficacy under clinical studies for some of the tau aggregation inhibitors including the GSK3-β inhibitor trials have already surfaced [42,43].”
Background
Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease –conformist, nonconformist, and realistic prospects for AD pathogenesis
Li, H., Liu, C.-C., Zheng, H., & Huang, T. Y. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0139-3 · Cited by 103
“Although selective tau-aggregation blockers [246] or tau-reactive antibodies (https:// clinicaltrials.”
Background
Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets
Fišar, Z. (2022) · Biomolecules · doi:10.3390/biom12111676 · Cited by 113
“, inhibition of tau aggregation may be involved in the effects of methylene blue [337,401], red gingseng [402], crocin [403], cinnamaldehyde and epicatechin [404], purpurin [405], and folate [406], and inhibition of Aβ toxicity may be involved in the effects of resveratrol [407], huperzine A (cholinesterase inhibitor…”
Background
Advances in Alzheimer’s disease’s pharmacological treatment
Filho, C. E. C., Loss, L. B., Pereira, C. M., Rossoni, J. V., Barcelos, R. M., Chiarelli-Neto, O., da Silva, B. S., Ambrósio, R. P., Castro, F. C. D. A. Q., Teixeira, S. F., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1101452 · Cited by 107
Alzheimer’s disease (AD) therapeutics – 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.026 · Cited by 98
Targeting tau: clinical trials and novel therapeutic approaches
VandeVrede, L., Boxer, A. L., & Polydoro, M. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.134919 · Cited by 90
Eyetracking Metrics in Young Onset Alzheimer’s Disease: A Window into Cognitive Visual Functions
Pavisic, I. M., Firth, N. C., Parsons, S., Martínez‐Rego, D., Shakespeare, T. J., Yong, K. X. X., Slattery, C. F., Paterson, R. W., Foulkes, A., Macpherson, K., et al. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00377 · Cited by 96
Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease
Toniolo, S., Sen, A., & Husain, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239318 · Cited by 97
“LMTM (or Methylene Blue or TRx0237), an aggregator inhibitor, did not prove beneficial in large human trials in AD [102], even if subsequent analyses suggested a possible positive effect on rates of brain atrophy [103], and currently a phase 1b/2a is ongoing in mild cognitive impairment (MCI) and mild AD (Table 1).”
Background
Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21
Sun, Y., Wang, Y., Chen, S., Chen, Y., Shen, J., Yao, W., Gao, X., & Chen, S. (2020) · Theranostics · doi:10.7150/thno.44370 · Cited by 95
“Unfortunately, in recent years, most mono-target drug candidates designed directly for Aβ or tau have not achieved desirable efficiency in clinical trials [7, 8].”
Background
Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease
Soeda, Y., Saito, M., Maeda, S., Ishida, K., Nakamura, A., Kojima, S., & Takashima, A. (2019) · Journal of Alzheimer’s Disease · doi:10.3233/jad-181001 · Cited by 84
The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation
Karvandi, M. S., Hesari, F. S., Aref, A. R., & Mahdavi, M. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1105247 · Cited by 97
“NCT01689246 TRx0237 Tau aggregation inhibitor (Hung and Fu, 2017) Oral AD III Completed No evidence of benefits for patients with mild to moderate Alzheimer’s disease (Gauthier et al., 2016)”
Background
Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer’s disease in bladder cancer patients
Gofrit, O. N., Klein, B., Cohen, I. R., Ben‐Hur, T., Greenblatt, C. L., & Bercovier, H. (2019) · PLoS ONE · doi:10.1371/journal.pone.0224433 · Cited by 89
Drug development for Alzheimer’s disease: Review
Lao, K., Ji, N., Zhang, X., Qiao, W., Tang, Z., & Gou, X. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2018.1474361 · Cited by 86
“The results of phase III trial completed in 2016 failed to suggest benefit of LMTM as an addon treatment for patients with mild-to-moderate AD [77].”
Background
Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 89
The Neurotoxic Role of Extracellular Tau Protein
Sebastián‐Serrano, Á., de Diego-García, L., & Díaz-Hernández, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19040998 · Cited by 85
“In fact, it has been reported that a tau aggregation blocker failed to induce benefits in phase III trials [97].”
Background
Transplantation of Human Menstrual Blood-Derived Mesenchymal Stem Cells Alleviates Alzheimer’s Disease-Like Pathology in APP/PS1 Transgenic Mice
Zhao, Y., Chen, X., Wu, Y., Wang, Y., Li, Y., & Xiang, C. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00140 · Cited by 79
“However, there are no effective therapies for AD involving pharmacological agents that target either Aβ or tau aggregation inhibitors (Doody et al., 2014; Salloway et al., 2014; Lovestone et al., 2015; Gauthier et al., 2016).”
Background
Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer's Disease
Wu, X., Piña-Crespo, J., Zhang, Y., Chen, X., & Xu, H. (2017) · Chinese Medical Journal · doi:10.4103/0366-6999.220313 · Cited by 82
“TRx 0237 (LMTXTM) Tau aggregation inhibitor Phase 3 Failed to improve cognition Gauthier et al.[118]”
Background
Upregulation of RIN3 induces endosomal dysfunction in Alzheimer’s disease
Shen, R., Zhao, X., He, L., Ding, Y., Xu, W. L., Lin, S., Fang, S., Yang, W., Sung, K., Spencer, B. J., et al. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00206-1 · Cited by 81
Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010–2020)
Li, Y., Sang, S., Ren, W., Pei, Y., Bian, Y., Chen, Y., & Sun, H. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113874 · Cited by 77
Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review
Hodges, J. R., & Piguet, O. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171087 · Cited by 79
A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 76
Disrupted hippocampal growth hormone secretagogue receptor 1α interaction with dopamine receptor D1 plays a role in Alzheimer′s disease
Tian, J., Guo, L., Sui, S., Driskill, C., Phensy, A., Wang, Q., Gauba, E., Zigman, J. M., Swerdlow, R. H., Kroener, S., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav6278 · Cited by 72
Anti-Tau Trials for Alzheimer's Disease: A Report from the EU/US/CTAD Task Force
Cummings, J. L., Blennow, K., Johnson, K. A., Keeley, M. B., Bateman, R. J., Molinuevo, J. L., Touchon, J., Aisen, P. S. S., & Vellas, B. J. (2019) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2019.14 · Cited by 72
Pharmacotherapy of Alzheimer’s Disease: Seeking Clarity in a Time of Uncertainty
Ibrahim, N. H., Yahaya, M. F., Mohamed, W. M. Y., Teoh, S. L., Hui, C. K., & Kumar, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00261 · Cited by 77
Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer’s Disease and Hearing Loss: A Multicenter Controlled Randomized Trial
Nguyen, M.-F., on behalf of the ADPHA study group, Bonnefoy, M., Adrait, A., Gueugnon, M., Petitot, C., Collet, L., Roux, A. S., & Perrot, X. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160793 · Cited by 70
Targeting the ensemble of heterogeneous tau oligomers in cells: A novel small molecule screening platform for tauopathies
Lo, C. H., Lim, C. K., Ding, Z., Wickramasinghe, S. P., Braun, A. R., Ashe, K. H., Rhoades, E. R., Thomas, D. D., & Sachs, J. N. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.06.4954 · Cited by 65
“Of these small molecules, only methylene blue advanced to phase III clinical trials, albeit with unsuccessful results [39].”
Background
Dysregulation of Rab5‐mediated endocytic pathways in Alzheimer's disease
Xu, W. L., Fang, F., Ding, J., & Wu, C. (2018) · Traffic · doi:10.1111/tra.12547 · Cited by 72
“However, these efforts have also failed in recent clinical trials.(18) Nevertheless,”
Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not
Sang, S., Pan, X., Chen, Z., Zeng, F., Pan, S., Liu, H., Jin, L., Fei, G., Wang, C., Ren, S., et al. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0354-2 · Cited by 70
Royal Jelly Alleviates Cognitive Deficits and β-Amyloid Accumulation in APP/PS1 Mouse Model Via Activation of the cAMP/PKA/CREB/BDNF Pathway and Inhibition of Neuronal Apoptosis
You, M., Pan, Y., Liu, Y., Chen, Y., Wu, Y., Si, J., Wang, K., & Hu, F. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00428 · Cited by 70
“Likewise, tau aggregation inhibitors failed to improve the memory and cognitive function during AD progression (Gauthier et al., 2016).”
Background
Molecular mechanisms of proteinopathies across neurodegenerative disease: a review
Marsh, A. (2019) · Neurological Research and Practice · doi:10.1186/s42466-019-0039-8 · Cited by 64
Tau-targeting therapy in Alzheimer’s disease: Critical advances and future opportunities
Guo, Y., Li, S., Zeng, L.-H., & Tan, J. (2022) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2022.16 · Cited by 61
Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target
Oakley, S. S., Maina, M. B., Marshall, K. E., Al‐Hilaly, Y. K., Harrington, C., Wischik, C. M., & Serpell, L. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.590754 · Cited by 59
“LMTM was found to produce better outcomes when given as a monotherapy than as an add-on to symptomatic AD treatments (269, 270).”
BackgroundSelf-citation
Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSweMouse Models of Tauopathy and Amyloidosis
Briggs, D. I., Defensor, E., Memar Ardestani, P., Yi, B., Halpain, M., Seabrook, G., & Shamloo, M. (2017) · eneuro · doi:10.1523/eneuro.0025-17.2017 · Cited by 61
“Despite the pressing need for more targeted treatments, to date, all Phase III clinical trials testing therapeutics directed at the neuropathological substrates of AD have failed (Mullane and Williams, 2013; Gauthier et al., 2016).”
Background
Recent Progress in the Pharmacotherapy of Alzheimer’s Disease
Khoury, R., Patel, K., Gold, J., Hinds, S., & Grossberg, G. T. (2017) · Drugs & Aging · doi:10.1007/s40266-017-0499-x · Cited by 62
Self-assembly hollow manganese Prussian white nanocapsules attenuate Tau-related neuropathology and cognitive decline
Cai, X., Zhang, K., Xie, X., Zhu, X., Feng, J., Jin, Z., Zhang, H., Tian, M., & Chen, H. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119678 · Cited by 59
Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease
Martínková, J., Quevenco, F., Karcher, H., Ferrari, A., Sandset, E. C., Szoeke, C. E. I., Hort, J., Schmidt, R., Chadha, A. S., & Ferretti, M. T. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.24124 · Cited by 65
Recent Advances in Drug Development for Alzheimer’s Disease: A Comprehensive Review
Xing, H., Yue, S., Qin, R., Du, X., Wu, Y., Zhangsun, D., & Luo, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083905 · Cited by 66
“For example, the overall safety of leuco-methylthioninium (LMT) as a monotherapy has several drawbacks, with adverse events affecting the gastrointestinal and urinary tracts being the most common and the most common reason for the cessation of high doses of LMTM [96].”
Hyperphosphorylated tau aggregation and cytotoxicity modulators screen identified prescription drugs linked to Alzheimer's disease and cognitive functions
Liu, M., Dexheimer, T. S., Sui, D., Hovde, S., Deng, X., Kwok, R. P. S., Bochar, D. A., & Kuo, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-73680-2 · Cited by 59
Recent advancement in therapeutic strategies for Alzheimer’s disease: Insights from clinical trials
Khan, T., Waseem, R., Shahid, M., Ansari, J., Ahanger, I. A., Hassan, M. I., & Islam, A. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102113 · Cited by 60
M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer's disease?
Scarpa, M., Hesse, S., & Bradley, S. J. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2019.12.003 · Cited by 55
Insights into the use of biomarkers in clinical trials in Alzheimer's disease
Pascoal, T. A., Aguzzoli, C. S., Lussier, F. Z., Crivelli, L., Suemoto, C. K., Fortea, J., Rosa‐Neto, P., Zimmer, E. R., Ferreira, P. C. L., & Bellaver, B. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105322 · Cited by 60
Drug delivery strategies with lipid-based nanoparticles for Alzheimer’s disease treatment
Jang, Y.-J., Kang, S.-J., Park, H. S., Lee, D., Kim, J. H., Kim, J.-E., Kim, D., Chung, C., Yoon, J., & Bhang, S. H. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03109-3 · Cited by 64
The Potentials of Methylene Blue as an Anti-Aging Drug
Xue, H., Thaivalappil, A., & Cao, K. (2021) · Cells · doi:10.3390/cells10123379 · Cited by 56
“However, the result was inconclusive due to the lack of using the proper placebo control group [62].”
Background
Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease
Peña‐Díaz, S., García‐Pardo, J., & Ventura, S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030839 · Cited by 54
Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer’s disease
Pradeepkiran, J. A., Reddy, A. P., & Reddy, P. H. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.11.005 · Cited by 53
Highly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau
Rosenqvist, N., Asuni, A. A., Andersson, C. R., Christensen, S., Daechsel, J. C. A., Egebjerg, J., Falsig, J., Helboe, L., Jul, P., Kartberg, F., et al. (2018) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.09.005 · Cited by 52
“In light of failed clinical trials using small molecules to inhibit tau phosphorylation (glycogen synthase kinase 3 inhibitor [41]) or aggregation (leuco-methylthioninium bis [42]), immunotherapy targeting the propagation of tau pathology offers an attractive new endeavor to treat AD.”
Background
Four-Repeat Tauopathies: Current Management and Future Treatments
VandeVrede, L. A., Ljubenkov, P. A., Rojas, J. C., Welch, A. E., & Boxer, A. L. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00888-5 · Cited by 55
A Pilot Study of Whole-Brain Low-Intensity Pulsed Ultrasound Therapy for Early Stage of Alzheimer’s Disease (LIPUS-AD): A Randomized, Double-Blind, Placebo-Controlled Trial
Shimokawa, H., Shindo, T., Ishiki, A., Tomita, N., Ichijyo, S., Watanabe, T., Nakata, T., Eguchi, K., Kikuchi, Y., Shiroto, T., et al. (2022) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.2022.j078 · Cited by 51
Small-molecule drugs development for Alzheimer's disease
Yao, W., Yang, H., & Yang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1019412 · Cited by 54
“LMTX (TRx0237), a stable reduced form of the methylthioninium (MT) moiety, has been extensively studied as a tau aggregation inhibitor (Gauthier et al., 2016).”
Background
Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology
Huang, Y., Wen, J., Ramirez, L.-M., Gümüşdil, E., Pokhrel, P., Man, V. H., Ye, H., Han, Y., Liu, Y., Li, P., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41241-6 · Cited by 49
Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate
Wischik, C. M., Bentham, P., Gauthier, S., Miller, S., Kook, K., & Schelter, B. O. (2022) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2022.63 · Cited by 55
Self-citation

Authors: Gauthier, S., Feldman, H. H., Schneider, L. S., Wilcock, G. K., Frisoni, G. B., Hardlund, J. H., Moebius, H. J., Bentham, P., Kook, K. A., Wischik, D. J., Schelter, B. O., Davis, C. S., Staff, R. T., Bracoud, L., Shamsi, K., Storey, J. M. D., Harrington, C. R., & Wischik, C. M.
Affiliations: Douglas Mental Health University Institute (CA)
University of California San Diego (US)
University of Southern California (US)
University of Oxford (GB)
University of Geneva (CH)
TauRx (United Kingdom) (GB)
University of Aberdeen (GB)
Corresponding author: Wischik, Claude M
ORCID: Gauthier, Serge
Feldman, Howard H
Schneider, Lon S
Wilcock, Gordon K
Frisoni, Giovanni B
Moebius, Hans J
Bentham, Peter
Staff, Roger T
Bracoud, Luc
Shamsi, Kohkan
Storey, John M D
Harrington, Charles R
Venue: The Lancet
Publisher: Elsevier BV
Published: 2016-12
Volume: 388
Issue: 10062
Pages: 2873-2884
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(16)31275-2
PMC: PMC5164296
OpenAlex: W2553774099
Cited by: 427
References: 31
Citations by year: 2026: 25 · 2025: 46 · 2024: 47 · 2023: 41 · 2022: 47 · 2021: 46 · 2020: 48 · 2019: 47 · 2018: 48 · 2017: 27 · 2016: 4
FWCI: 33.77
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
Archive ouverte UNIGE (University of Geneva) (publishedVersion)
PubMed Central (acceptedVersion)
Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders: TauRx Pharmaceuticals
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
Keywords: Alzheimer's disease, tau aggregation, methylene blue, disease progression, ADAS-Cog, cognitive decline, activities of daily living, methemoglobinemia, drug safety, mild to moderate Alzheimer's disease, amyloid PET, FDG-PET
MeSH terms: Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, tau Proteins, Treatment Failure, Mice

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.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks