The DOI matches its Crossref record; 232 of the 235 references it cites were found in a registry or an index; 13 of the 230 sources its claims cite were checked for support.
Tau-targeting therapies for Alzheimer disease
Open accessAbstract
Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically.Interest in tau-targeting strategies for Alzheimer disease is increasing, in part because of the failure of various amyloid-β-targeting treatments in clinical trials. Congdon and Sigurdsson review the current status of tau-targeting therapies, including anti-tau drugs and immunotherapies.Key pointsTherapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β (Aβ)-targeting to tau-targeting approaches.Early anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy.Most of the tau-targeting approaches that are currently in clinical trials are immunotherapies.Tau is likely to be a better target than Aβ once cognitive deficits manifest because the tau burden correlates better with clinical impairments than does the Aβ burden.Eventually, with continued improvements in diagnostics, both Aβ and tau are likely to be targeted prophylactically for clearance.
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TL;DR
This review summarizes tau-targeting therapies for Alzheimer disease, covering tau pathological mechanisms and clinical-stage drugs. It concludes that after Aβ-targeting failures and discontinuation of many early anti-tau approaches, tau immunotherapies now dominate clinical trials and show promise, though human efficacy remains to be established.
Key findings
Tau pathology correlates better with cognitive impairment and neuron loss than Aβ lesions, so targeting tau is expected to be more effective than Aβ clearance once symptoms are evident. Most tau-targeting therapies in clinical trials are immunotherapies; earlier kinase inhibitors, aggregation inhibitors, and microtubule stabilizers were mostly discontinued because of toxicity and/or lack of efficacy. In reported trials, tideglusib produced no significant improvement in the full AD cohort but showed cognitive improvement and reduced CSF β-secretase in a mild AD subgroup; LMTX showed no significant benefits in two phase III trials; AADvac1 phase I elicited IgG in 29 of 30 patients, with no encephalitis or oedema but two withdrawals due to adverse reactions. MK-8719 increased O-GlcNAcylated proteins dose-dependently in healthy individuals, was well tolerated, and received FDA orphan drug status for PSP.
Methods
Narrative review of tau-targeting therapies for AD and other tauopathies, focusing on mechanisms such as post-translational modifications, cytoskeletal dysfunction, tau aggregation, and impaired protein degradation. Synthesizes preclinical and clinical literature, including published trial results and ClinicalTrials.gov registrations; no primary data collection or systematic search is described. Discusses active and passive immunotherapies and other drug classes, with tables of ongoing, completed, and discontinued trials.
Limitations
The paper states that preclinical success in animal models has often failed to translate into human benefit; clinical data on methylene blue derivatives are not very promising, and curcumin is limited by bioavailability and has not demonstrated efficacy in humans with tauopathy. It also notes that some trial results are unpublished or awaited, that LMTX subgroup claims were widely questioned over statistics and unsuitable controls, that decreasing CSF tau with AD progression may impede detection of drug-induced reductions, and that it is unclear how closely tau seeding/spread is linked to tau toxicity. Evident from the text: this is a narrative review without systematic search or quantitative synthesis, and its 2018 publication date means the clinical trial landscape described is now dated.
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Claims the paper makes
99 Not checked yet · 20 Own interpretation · 9 No basis given · 3 Partly supported · 2 Supported so far · 2 Own method · 2 Own result · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CSF tau levels are not increased in non-AD tauopathies57–60, suggesting that extracellular tau is not a primary target in these conditions.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [57] Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445–1452 (2012). source
- Partly supportedcites [58] Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations — progress and challenges. Prog. Neurobiol. 95, 636–648 (2011). sourceExperimental — accuracy not yet measured
Section 3 (page unavailable) reports normal CSF tau levels in patients with FTLD-Tau. Section 4 says FTLD disorders lack a clear extracellular target for ligand binding, supporting the suggested inference for FTLD. The paper does not establish that extracellular tau is not a primary target across all non-AD tauopathies. (LLM, conf=0.82)
- Could not verifycites [59] Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016). sourceExperimental — accuracy not yet measured
The Core biomarkers section reports elevated CSF tau in Alzheimer’s disease compared with controls, but does not address extracellular tau as a treatment target in non-AD tauopathies. Searches for non-AD tauopathies and extracellular tau targets found no passage in our copy that supports the quoted conclusion. (LLM, conf=0.73)
- Partly supportedcites [60] Wagshal, D. et al. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiatry 86, 244–250 (2015). sourceExperimental — accuracy not yet measured
The Introduction and Discussion report that CSF tau in progressive supranuclear palsy is comparable to or lower than in controls, supporting the citing sentence’s premise. They do not establish that extracellular tau is not a primary therapeutic target in non-AD tauopathies; that is the citing authors’ inference from the CSF finding. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the latest phase II/III study162, patients with PSP were treated with NAP for 52 weeks, but no differences were found between placebo-treated and NAP-treated patients163.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Microtubule stabilizers
What the sources say
- Not checked yetcites [162] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01110720 (2013).
- Partly supportedcites [163] Boxer, A. L. et al. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 13, 676–685 (2014). sourceExperimental — accuracy not yet measured
The Discussion reports no effect of 52 weeks of davunetide on the primary and secondary outcomes in patients with PSP. The claim's unqualified statement that there were no differences between groups overlooks the small differences in nasal adverse-event rates that the paper reports. (LLM, conf=0.86)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Active tau immunization has been shown to reduce tau pathology by targeting single185, 187, 189–193 or multiple194 phospho-epitopes, the amino terminus195, full-length normal and mutant tau196, 197, or aggregated tau198.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Supportedcites [185] Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007). source
The Introduction describes immunizing P301L mice with a phosphorylated tau epitope. The Tau pathology section reports reduced MC1 and PHF1 immunoreactivity in immunized mice. This supports the single phospho-epitope portion of the citing sentence; its other targets have separate citations. (LLM, conf=0.91)
- Not checked yetcites [187] Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).
- Supportedcites [189] Bi, M., Ittner, A., Ke, Y. D., Gotz, J. & Ittner, L. M. Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice. PLoS ONE 6, e26860 (2011). source
The Discussion reports that immunization with a peptide containing the Ser396/Ser404 dual phospho-epitope reduced tau phosphorylation and neurofibrillary tangles in P301L tau transgenic mice. This supports the phospho-epitope portion of the multi-citation sentence; the other targets are attributed to other citations. (LLM, conf=0.91)
- Supportedcites [190] Theunis, C. et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy. PLoS ONE 8, e72301 (2013). source
This citation is attached to the ‘multiple phospho-epitopes’ portion of the sentence, not the other targets listed. The Discussion (Specificity & Efficacy; page unavailable) identifies the ACI-35 vaccine antigen as phosphorylated at S396 and S404. The Results (Efficacy: Brain pathology; page unavailable) report reduced tau pathology in vaccinated mice, particularly tau phosphorylated at S396; S404 levels were not markedly affected. (LLM, conf=0.91)
- Supportedcites [191] Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J. Neurosci. 30, 16559–16566 (2010). source
The citation appears in the group supporting immunization targeting a phospho-epitope, not the later examples involving the amino terminus or full-length tau. The Results report that mice immunized with a tau peptide bearing an AD phospho-epitope had reduced pathological tau, including a 57% reduction in PHF1-reactive aggregates in the pyriform cortex compared with identical controls. (LLM, conf=0.90)
- Not checked yetcites [192] Troquier, L. et al. Targeting phospho-Ser422 by active tau immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr. Alzheimer Res. 9, 397–405 (2012). source
- Supportedcites [193] Rajamohamedsait, H., Rasool, S., Rajamohamedsait, W., Lin, Y. & Sigurdsson, E. M. Prophylactic active tau immunization leads to sustained reduction in both tau and amyloid-β pathologies in 3xTg mice. Sci. Rep. 7, 17034 (2017). source
The Introduction reports active immunization of 3xTg mice with a phosphorylated tau peptide, Tau379–408[P-Ser396,404]. The Results section reports a reduction in tau aggregates. This source supports the phospho-epitope example to which its citation is attached; the other targets in the sentence have separate citations. (LLM, conf=0.90)
- Not checked yetcites [194] Boimel, M. et al. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp. Neurol. 224, 472–485 (2010). source
- Supportedcites [195] Davtyan, H. et al. MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice. Vaccine 35, 2015–2024 (2017). source
Citation 195 is attached to the amino-terminus part of the sentence, not the other vaccine targets. The Introduction identifies AV-1980D as a vaccine targeting tau’s N-terminus (amino acids 2–18), and Results §3.2 reports significantly reduced total human tau in vaccinated THY-Tau22 mice compared with controls. Page numbers are not available in our copy. (LLM, conf=0.92)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“However, several groups have reported that antibodies, including anti-tau antibodies, can enter neurons, and that extracellular tau might be important for the spread of tau pathology227–229.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [227] Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer’s disease. Trends Mol. Med. 21, 394–402 (2015). source
- Supportedcites [228] Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013). source
In “The seeded initiation and spread of tauopathy in vivo,” the paper says tau likely transfers between cells after release into and uptake from the extracellular space. “Transcellular propagation of tau aggregation in vitro” further describes extracellular tau aggregates being taken up by recipient cells and propagating aggregation, supporting the claim's cautious wording. Page numbers are not provided in our copy. (LLM, conf=0.94)
- Could not verifycites [229] Sigurdsson, E. M. Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J. Alzheimers Dis. 15, 157–168 (2008). sourceExperimental — accuracy not yet measured
The “Targeting Pathological Tau Protein by Immunotherapy” section says tangles can be found extracellularly after neuronal death. “Mechanism of Clearance” proposes that clearing extracellular tangles may reduce associated pathology, but neither passage says extracellular tau helps spread tau pathology. Searches for extracellular tau and pathology spread or propagation found no passage addressing that point. (LLM, conf=0.72)
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In the paper
“Some data indicate that Aβ immunotherapy has noteworthy but modest effects on tau pathology.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
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In the paper
“in phase II trials, the anti-Aβ antibody bapineuzumab reduced CSF phospho-tau levels in patients with AD182,183”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [182] Blennow, K. et al. Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch. Neurol. 69, 1002–1010 (2012). source
- Not checked yetcites [183] Salloway, S. et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73, 2061–2070 (2009). source
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In the paper
“Moreover, antibody fragments have been shown to reduce tau levels in vivo225,226.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [225] Nisbet, R. M. et al. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140, 1220–1330 (2017). source
- Not checked yetcites [226] Ising, C. et al. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J. Exp. Med. 214, 1227–1238 (2017). source
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In the paper
“In the first active immunization trial, the AN-1792 vaccine seemed to show some ability to clear Aβ plaque-associated tau lesions through plaque removal179–181”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [179] Serrano-Pozo, A. et al. Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain 133, 1312–1327 (2010). source
- Not checked yetcites [180] Boche, D., Denham, N., Holmes, C. & Nicoll, J. A. Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis. Acta Neuropathol. 120, 369–384 (2010). source
- Not checked yetcites [181] Boche, D. et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Aβ42 immunisation in Alzheimer’s disease. Acta Neuropathol. 120, 13–20 (2010). source
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In the paper
“The first reports of successful active and passive immunization against tau in a tauopathy mouse model, using a phospho-tau peptide comprising the pSer396/404 epitope or the PHF1 antibody against this epitope185–188, came from our group.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [185] Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007). source
- Not checked yetcites [186] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658–667 (2011). source
- Not checked yetcites [187] Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).
- Not checked yetcites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).
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In the paper
“these results did not extend to phase III trials, in which bapineuzumab had no effect on tau pathology184”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [184] Vandenberghe, R. et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res. Ther. 8, 18 (2016). source
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In the paper
“Similar tau immunogens administered with a milder adjuvant or fewer immunizations do not produce such adverse reactions194,196”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [194] Boimel, M. et al. Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp. Neurol. 224, 472–485 (2010). source
- Not checked yetcites [196] Selenica, M. L. et al. Epitope analysis following active immunization with tau proteins reveals immunogens implicated in tau pathogenesis. J. Neuroinflamm. 11, 152 (2014). source
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In the paper
“Epitope mapping revealed that DC8E8 binds a six-amino-acid sequence, HXPGGG, which is found in each of the microtubule-binding repeats of tau.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
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In the paper
“Furthermore, tau is now known to be present in the interstitial space both in tauopathy animal models234 and in the human brain236.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [234] Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).
- Not checked yetcites [236] Herukka, S. K. et al. Amyloid-β and tau dynamics in human brain interstitial fluid in patients with suspected normal pressure hydrocephalus. J. Alzheimers Dis. 46, 261–269 (2015). source
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In the paper
“Fc receptors are expressed on neurons231,232 and seem to be the main route of entry for anti-tau antibodies: blockade of low-affinity FcγII/III receptors largely prevents antibody uptake202,219.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [202] Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013). source
- Not checked yetcites [219] Kondo, A. et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436 (2015). source
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In the paper
“Of note, binding of a tau–antibody complex to a cytosolic Fc receptor, E3 ubiquitin-protein ligase TRIM21, promotes proteosomal degradation of the complex, thereby inhibiting intracellular seeded tau aggregation233.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [233] McEwan, W. A. et al. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc. Natl Acad. Sci. USA 114, 574–579 (2017). source
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In the paper
“Indeed, several reports are available of antibodies that are capable of reducing tau levels and preventing spreading without apparently entering neurons216,218,239.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [216] Castillo-Carranza, D. L. et al. Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014). source
- Not checked yetcites [218] d’Abramo, C., Acker, C. M., Jimenez, H. T. & Davies, P. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS ONE 8, e62402 (2013). source
- Not checked yetcites [239] Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl Neurol. 2, 278–288 (2015). source
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In the paper
“However, several groups have reported that antibodies, including anti-tau antibodies, can enter neurons, and that extracellular tau might be important for the spread of tau pathology227–229.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [227] Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer’s disease. Trends Mol. Med. 21, 394–402 (2015). source
- Not checked yetcites [228] Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013). source
- Not checked yetcites [229] Sigurdsson, E. M. Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J. Alzheimers Dis. 15, 157–168 (2008). source
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In the paper
“In animal models that express tau only in certain brain regions, or that are injected with exogenous tau, spreading of tau pathology to anatomically connected regions occurs over time54,64,228.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [64] Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017). source
- Not checked yetcites [228] Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013). source
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In the paper
“Multiple groups have employed antibodies in cell and animal models to block this spreading by targeting extracellular tau238.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [238] Sigurdsson, E. M. Tau immunotherapy. Neurodegener. Dis. 16, 34–38 (2016). source
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In the paper
“For example, despite encouraging results in preclinical studies, the clinical data on methylene blue derivatives are not very promising.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
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In the paper
“To some extent, this strategy is already possible, as has been shown in Aβ-targeting clinical trials involving carriers of mutations associated with familial AD, and in control individuals with PET evidence of Aβ accumulation.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
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In the paper
“A shift in the timing of intervention to the MCI stage or the very early stages of AD has been a feature of many recent trials, and as diagnostic methods continue to improve, treatment before symptom onset might be feasible.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
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In the paper
“The developers of BMS-986168 observed that neurons derived from stem cells of patients with familial AD secreted amino-terminal tau fragments, termed e-tau215.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [215] Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015). source
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In the paper
“Similar results were seen when a higher dose was delivered systemically239.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [239] Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl Neurol. 2, 278–288 (2015). source
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In the paper
“Phase I testing of C2N-8E12 in patients with PSP did not show any major adverse effects or safety issues compared with placebo252.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [252] West, T. et al. Safety, tolerability and pharmacokinetics of ABBV-8E12, a humanized anti-tau monoclonal antibody, in a Phase I, single ascending dose, placebo-controlled study in subjects with progressive supranuclear palsy. J. Prev. Alzheimers Dis. 3, 285 (2016).
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In the paper
“In initial tests in humans, MK-8719 was able to increase the levels of O-GlcNAcylated proteins, and the results of efficacy studies are eagerly awaited.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
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In the paper
“In cell culture, C2N-8E12 prevented pathological tau seeding caused by exogenous tau aggregates212.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [212] Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012). source
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In the paper
“In addition, mass spectroscopy studies indicate that CSF tau predominantly consists of tau fragments spanning amino acids 150–250 of the tau protein, with the amino and carboxyl termini presumably having been digested264,265.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
What the sources say
- Not checked yetcites [264] Barthelemy, N. R. et al. differential mass spectrometry profiles of tau protein in the cerebrospinal fluid of patients with Alzheimer’s disease, progressive supranuclear palsy, and dementia with lewy bodies. J. Alzheimers Dis. 51, 1033–1043 (2016). source
- Not checked yetcites [265] Barthelemy, N. R. et al. Tau protein quantification in human cerebrospinal fluid by targeted mass spectrometry at high sequence coverage provides insights into its primary structure heterogeneity. J. Proteome Res. 15, 667–676 (2016). source
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In the paper
“In AD, deposition of tau aggregates follows a highly stereotyped pattern, beginning in the entorhinal cortex and hippocampus before spreading to other regions11,12.”
§ Tau-targeting therapies for Alzheimer disease > Pathological processes in tauopathies
What the sources say
- Not checked yetcites [11] Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). source
- Not checked yetcites [12] Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997). source
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In the paper
“For example, evidence from post-mortem tissue from the brains of patients with AD indicates that levels of active cyclin-dependent-like kinase 5 (CDK5) and cyclin-dependent kinase 5 activator 1, p25 — a truncated form of a CDK5 regulator — are increased in disease28.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [28] Shukla, V., Skuntz, S. & Pant, H. C. Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch. Med. Res. 43, 655–662 (2012). source
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In the paper
“Although many tau kinases have been identified, protein phosphatase 2A (PP2A) is one of only a few tau phosphatases, and is responsible for over 70% of the total tau phosphatase activity33.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [33] Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C. X. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942–1950 (2005). source
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In the paper
“In brain tissue from patients with AD, compared with healthy elderly controls, levels of O-GlcNAcylated tau are reduced40.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [40] Liu, F. et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132, 1820–1832 (2009). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Impairment of protein degradation pathways, including autophagy (reviewed previously66–68), is found in a host of neurodegenerative diseases.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [66] Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J. & Sargeant, T. J. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer’s disease? J. Neurochem. 140, 703–717 (2017). source
- Not checked yetcites [67] Zare-Shahabadi, A., Masliah, E., Johnson, G. V. & Rezaei, N. Autophagy in Alzheimer’s disease. Rev. Neurosci. 26, 385–395 (2015). source
- Not checked yetcites [68] Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the case of AD, Aβ promotes caspase activation, thereby providing a link between the two main pathologies36.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [36] Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005). source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For example, the documented decrease in CSF tau with pathology progression in patients with AD might impede the detection of drug-induced reductions in CSF tau.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
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In the paper
“It also raises concerns about the validity of targeting extracellular tau in the later stages of the disease.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
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In the paper
“Overall, in humans, tau aggregation and the presence of NFTs correlate more closely with symptom severity and neuron loss than do Aβ lesions49.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [49] Nelson, P. T. et al. Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J. Neuropathol. Exp. Neurol. 66, 1136–1146 (2007). source
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In the paper
“Disruption of autophagic flux and a failure of autophagosomes to fuse with lysosomes leads to a build-up of vesicles, which can be seen in dystrophic neurites and cell bodies in AD, CBD and PSP, as well as in tauopathy models73–76.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [73] Boland, B. et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J. Neurosci. 28, 6926–6937 (2008). source
- Not checked yetcites [74] Sanchez-Varo, R. et al. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus. Acta Neuropathol. 123, 53–70 (2012). source
- Not checked yetcites [75] Bordi, M. et al. Autophagy flux in CA1 neurons of Alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy 12, 2467–2483 (2016). source
- Not checked yetcites [76] Piras, A., Collin, L., Gruninger, F., Graff, C. & Ronnback, A. Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. Commun. 4, 22 (2016). source
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In the paper
“CSF tau levels are not increased in non-AD tauopathies57–60, suggesting that extracellular tau is not a primary target in these conditions.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [57] Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445–1452 (2012). source
- Not checked yetcites [58] Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations — progress and challenges. Prog. Neurobiol. 95, 636–648 (2011). source
- Not checked yetcites [59] Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016). source
- Not checked yetcites [60] Wagshal, D. et al. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiatry 86, 244–250 (2015). source
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In the paper
“During the characterization of PHFs isolated from the brains of individuals with AD, it was discovered that tau had undergone carboxy-terminal truncation by caspase-336,37.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [36] Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005). source
- Not checked yetcites [37] Guo, T., Noble, W. & Hanger, D. P. Roles of tau protein in health and disease. Acta Neuropathol. 133, 665–704 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Data from cell and animal models show that tau is also a mediator of Aβ-induced toxicity46–48.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Cytoskeletal dysfunction
What the sources say
- Not checked yetcites [46] Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002). source
- Not checked yetcites [47] Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010). source
- Not checked yetcites [48] Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to being hyperphosphorylated, tau from patients with AD and other tauopathies is more heavily acetylated than in the brains of cognitively normal individuals8.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [8] Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the mature filaments are unlikely to be the primary toxic species: current evidence suggests that small soluble species are more detrimental to cells (reviewed previously54,55).”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [55] Cárdenas-Aguayo Mdel, C., Gómez-Virgilio, L., DeRosa, S. & Meraz-Ríos, M. A. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem. Neurosci. 5, 1178–1191 (2014). source
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In the paper
“In cell and animal models, siRNA was found to reduce tau pathology and associated functional impairments37.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Reducing tau expression
What the sources say
- Not checked yetcites [37] Guo, T., Noble, W. & Hanger, D. P. Roles of tau protein in health and disease. Acta Neuropathol. 133, 665–704 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As tau is a target of autophagy80, any deficiencies in processing could lead to increased levels of intracellular tau, including misfolded, damaged or aggregated protein.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [80] Wang, Y. & Mandelkow, E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 40, 644–652 (2012). source
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In the paper
“Interestingly, as with autophagic degradation, tau inhibits proteasome activity87”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [87] Deger, J. M., Gerson, J. E. & Kayed, R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 14, 715–724 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In two phase II trials151,152 in patients with AD, curcumin had no effect on cognition or CSF biomarkers149, and a third study in patients with MCI was terminated153.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Tau aggregation inhibitors
What the sources say
- Not checked yetcites [151] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00164749 (2008).
- Not checked yetcites [152] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00099710 (2009).
- Not checked yetcites [149] Hu, S. et al. Clinical development of curcumin in neurodegenerative disease. Expert Rev. Neurother. 15, 629–637 (2015). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In a pilot clinical study120, patients with AD who received 1,000 mg tideglusib daily showed significant improvements in cognition compared with placebo-treated patients121.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [120] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00948259 (2009).
- Not checked yetcites [121] del Ser, T. et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J. Alzheimers Dis. 33, 205–215 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting that tau pathology can become self-perpetuating once aggregates are present in neurons.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [87] Deger, J. M., Gerson, J. E. & Kayed, R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 14, 715–724 (2015). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The APP/PS1 mouse model of AD develops long-term potentiation (LTP) deficits, but rolipram-treated APP/PS1 mice showed comparable LTP induction to wild-type animals85.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Modulating protein degradation
What the sources say
- Not checked yetcites [85] Gurney, M. E., D’Amato, E. C. & Burgin, A. B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Neurotherapeutics 12, 49–56 (2015). source
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In the paper
“Methylene blue blocks the polymerization of tau in vitro by trapping the tau monomers in an aggregation-incompetent conformation137,138.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Tau aggregation inhibitors
What the sources say
- Not checked yetcites [137] Panza, F. et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. Biomed. Res. Int. 2016, 3245935 (2016). source
- Not checked yetcites [138] Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M. & Harrington, C. R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl Acad. Sci. USA 93, 11213–11218 (1996). source
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In the paper
“In addition, increased phosphorylation of PKA — a mediator of proteasome function — and proteasome subunits was seen after rolipram treatment, indicating enhancement of the proteasome system170.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Modulating protein degradation
What the sources say
- Not checked yetcites [170] Myeku, N. et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP–PKA signaling. Nat. Med. 22, 46–53 (2016). source
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In the paper
“The ubiquitin-proteasome system is also dysfunctional in AD, leading to a build-up of ubiquitinated proteins including tau81,82.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [81] Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 235, 1641–1644 (1987). source
- Not checked yetcites [82] Perry, G., Friedman, R., Shaw, G. & Chau, V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc. Natl Acad. Sci. USA 84, 3033–3036 (1987). source
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In the paper
“Although some notable treatment effects were observed in initial testing, in two phase III clinical trials of the methylene blue derivative LMTX (also known as LMTM or TRx0237)143,144, none of the treatment groups experienced significant benefits.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Tau aggregation inhibitors
What the sources say
- Not checked yetcites [143] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01689233 (2018).
- Not checked yetcites [144] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01689246 (2018).
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Data from the second completed phase III trial is expected to be forthcoming, although the first results presented at the Clinical Trials on Alzheimer’s Disease (CTAD) Congress in 2016 did not show slowing of disease progression with LMTX treatment147.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Tau aggregation inhibitors
What the sources say
- Not checked yetcites [147] Fagan, T. Tau inhibitor fails again — subgroup analysis irks clinicians at CTAD. Alzforum http://www.alzforum.org/news/conference-coverage/tau-inhibitor-fails-again-subgroup-analysis-irks-clinicians-ctad (2016).
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Another phase II trial of this drug123 was carried out in patients with PSP over 52 weeks, and no clinical improvements were observed124.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [123] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01049399 (2012).
- Not checked yetcites [124] Tolosa, E. et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov. Disord. 29, 470–478 (2014). source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Passive immunization also offers greater specificity for the epitope that is being targeted.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Patients will not develop their own antibodies, and the effects of immunization are likely to be transient, which reduces the risk of immunological adverse effects.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that any clearance of Aβ during active or passive immunization cannot reduce tau levels sufficiently to alter the course of disease, and direct targeting of tau is the next logical step.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Solanezumab did not alter tau levels in treated individuals in any of the trials.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Patients will not develop their own antibodies, and the effects of immunization are likely to be transient, which reduces the risk of immunological adverse effects.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident.”
§ Tau-targeting therapies for Alzheimer disease > Abstract
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Attempts to alter the disease course of AD by removing Aβ or reducing its production have been largely unsuccessful.
None of the sources cited for this claim have been checked yet.
In the paper
“At the low and mid-range doses, improvements in two measures of working memory were reported.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Modulating protein degradation
What the sources say
- Not checked yetcites [171] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02648672 (2017).
- Not checked yetcites [172] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02840279 (2017).
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Passive immunization offers a potential solution to the safety concerns that arise from active strategies.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Elicitation of antibodies against a native protein carries the risk of adverse immune reactions and detrimental targeting of the normal protein.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, treatments that prove efficacious in one condition could have wider applications.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Aβ is not a confounding variable in the non-AD tauopathies.
In the paper
“The epitope for development of the tau vaccine AADvac1 was selected on the basis of in vitro experiments using a monoclonal antibody, DC8E8, which prevents tau oligomerization240.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [240] Kontsekova, E., Zilka, N., Kovacech, B., Skrabana, R. & Novak, M. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res. Ther. 6, 45 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Antibodies could also modify disease progression by blocking the spread of tau pathology.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the most effective antibodies will probably be those that can also target tau inside the cell, where most of the pathological protein is located (Fig. 3 illustrates the potential intracellular and extracellular mechanisms).”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Researchers have known for decades that tau lesions begin in specific brain regions, before spreading to other areas11,12.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [11] Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). source
- Not checked yetcites [12] Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This type of spreading mechanism is thought to govern disease propagation in all amyloid diseases and related proteinopathies235.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [235] Sigurdsson, E. M., Wisniewski, T. & Frangione, B. Infectivity of amyloid diseases. Trends Mol. Med. 8, 411–413 (2002). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tau exocytosis provides a pool of pathologically relevant tau that can be targeted without requiring internalization.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The fact that NFTs are intracellular could potentially limit the utility of anti-tau antibodies as therapeutic agents.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, CSF tau levels are increased in AD but not in the other tauopathies57–60, suggesting that extracellular spread of tau pathology is not a prominent feature of non-AD tauopathies.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most efficacious antibodies are likely to be those that can target all pools of pathological tau protein, both intracellularly and extracellularly.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hence, an antibody selected to prevent tau seeding and spread may not necessarily block tau toxicity.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 57
- Probably not a substantial claim. 7
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“No adverse immune reactions were seen; in fact, microglial activation was reduced in the treated animals213,239.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Partly supportedcites [213] Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013). sourceExperimental — accuracy not yet measured
The Results (Correlation of multiple staining modalities; page not provided) report reduced microglial activation in several brain regions of antibody-treated mice compared with controls. The cited passages do not report an assessment of adverse immune reactions, so they do not establish that none occurred. (LLM, conf=0.84)
- Not checked yetcites [239] Yanamandra, K. et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann. Clin. Transl Neurol. 2, 278–288 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“Immunization with these agents reduced pathological tau levels and attenuated the behavioural phenotypes associated with the tauopathy, demonstrating the feasibility of these related interventions.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [185] Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007). source
- Not checked yetcites [186] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658–667 (2011). source
- Not checked yetcites [187] Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).
- Not checked yetcites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As mentioned above, the pSer396/404 region was the first to be studied and has since been targeted by several groups186, 188,201–208.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [186] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J. Neurochem. 118, 658–667 (2011). source
- Not checked yetcites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).
- Not checked yetcites [201] Chai, X. et al. Passive immunization with anti-tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457–34467 (2011). source
- Not checked yetcites [202] Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013). source
- Not checked yetcites [203] Congdon, E. E. et al. Affinity of tau antibodies for solubilized pathological tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy. Mol. Neurodegener 11, 62–86 (2016). source
- Not checked yetcites [204] Gu, J., Congdon, E. E. & Sigurdsson, E. M. Two novel tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce tau protein pathology. J. Biol. Chem. 288, 33081–33095 (2013). source
- Not checked yetcites [205] Ittner, A. et al. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J. Neurochem. 132, 135–145 (2015). source
- Not checked yetcites [206] Krishnamurthy, P. K., Deng, Y. & Sigurdsson, E. M. Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front. Psychiatry 2, 59 (2011). source
- Not checked yetcites [207] Liu, W. et al. Vectored intracerebral immunization with the anti-tau monoclonal antibody PHF1 markedly reduces tau pathology in mutant tau transgenic mice. J. Neurosci. 36, 12425–12435 (2016). source
- Not checked yetcites [208] Sankaranarayanan, S. et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS ONE 10, e0125614 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Reductions in pathological tau are achieved with few reported adverse effects, and the long-lasting immune response makes active immunization a promising option.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In mice, tau vaccination has been reported to cause toxicity when administered in conjunction with strong T-helper 1-inducing adjuvants199,200, which are not approved for use in humans.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [199] Rosenmann, H. et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch. Neurol. 63, 1459–1467 (2006). source
- Not checked yetcites [200] Rozenstein-Tsalkovich, L. et al. Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. Exp. Neurol. 248, 451–456 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, monoclonal antibodies against the amino-terminal or repeat domain (306–320) region209–215, oligomeric tau216,217, misfolded tau201,218,219, pSer202220,221, pThr231208 pSer409222, pSer413223 and pSer422224 have proved to be efficacious in tauopathy models.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [209] Subramanian, S., Savanur, G. & Madhavadas, S. Passive immunization targeting the N-terminal region of phosphorylated tau (residues 68–71) improves spatial memory in okadaic acid induced tauopathy model rats. Biochem. Biophys. Res. Commun. 483, 585–589 (2017). source
- Not checked yetcites [210] Dai, C. L. et al. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J. Neural Transm. 122, 607–617 (2015). source
- Not checked yetcites [211] Yanamandra, K. et al. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci. Transl Med. 9, eaal2029 (2017). source
- Not checked yetcites [212] Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012). source
- Not checked yetcites [213] Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013). source
- Not checked yetcites [214] Dai, C. L., Tung, Y. C., Liu, F., Gong, C. X. & Iqbal, K. Tau passive immunization inhibits not only tau but also Aβ pathology. Alzheimers Res. Ther. 9, 1 (2017). source
- Not checked yetcites [215] Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015). source
- Not checked yetcites [216] Castillo-Carranza, D. L. et al. Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014). source
- Not checked yetcites [217] Castillo-Carranza, D. L. et al. Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J. Alzheimers Dis. 40 (Suppl. 1), S97–S111 (2014). source
- Not checked yetcites [201] Chai, X. et al. Passive immunization with anti-tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457–34467 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“There was no evidence of an astrocyte response or significant differences in body weight in the vaccinated mice compared with vehicle-treated animals.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [190] Theunis, C. et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy. PLoS ONE 8, e72301 (2013). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Serum samples from Tau.P301L mice that were given two doses of ACI-35 contained antibodies that selectively bound pSer396/404 over the non-phosphorylated version of the epitope and could detect tau pathology when used in immunostaining experiments.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [190] Theunis, C. et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy. PLoS ONE 8, e72301 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Fc receptors are expressed on neurons231,232 and seem to be the main route of entry for anti-tau antibodies: blockade of low-affinity FcγII/III receptors largely prevents antibody uptake202,219.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [231] Fuller, J. P., Stavenhagen, J. B. & Teeling, J. L. New roles for Fc receptors in neurodegeneration — the impact on immunotherapy for Alzheimer’s disease. Front. Neurosci. 8, 235 (2014).
- Not checked yetcites [232] van der Kleij, H. et al. Evidence for neuronal expression of functional Fc (ε and γ) receptors. J. Allergy Clin. Immunol. 125, 757–760 (2010). source
- Not checked yetcites [202] Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013). source
- Not checked yetcites [219] Kondo, A. et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436 (2015). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The vaccinated animals showed a delay in the emergence of the motor phenotype, and also displayed a significant reduction in soluble tau phosphorylated at Ser396, but not at other amino acid residues.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [190] Theunis, C. et al. Efficacy and safety of a liposome-based vaccine against protein tau, assessed in tau. P301L mice that model tauopathy. PLoS ONE 8, e72301 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Our group and others have shown that anti-tau antibodies can cross into the brain and enter neurons, where they primarily colocalize with endosomal and lysosomal markers185,202–204,206,219,224,230.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [185] Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007). source
- Not checked yetcites [202] Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013). source
- Not checked yetcites [203] Congdon, E. E. et al. Affinity of tau antibodies for solubilized pathological tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy. Mol. Neurodegener 11, 62–86 (2016). source
- Not checked yetcites [204] Gu, J., Congdon, E. E. & Sigurdsson, E. M. Two novel tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce tau protein pathology. J. Biol. Chem. 288, 33081–33095 (2013). source
- Not checked yetcites [206] Krishnamurthy, P. K., Deng, Y. & Sigurdsson, E. M. Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front. Psychiatry 2, 59 (2011). source
- Not checked yetcites [219] Kondo, A. et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 523, 431–436 (2015). source
- Not checked yetcites [224] Collin, L. et al. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137, 2834–2846 (2014). source
- Not checked yetcites [230] Krishnaswamy, S. et al. Antibody-derived in vivo imaging of tau pathology. J. Neurosci. 34, 16835–16850 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Tau-expressing cells secrete normal and pathological tau234, which can be taken up by other cells and induce seeding of tau pathology54,64,228.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [234] Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [64] Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017). source
- Not checked yetcites [228] Walker, L. C., Diamond, M. I., Duff, K. E. & Hyman, B. T. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 70, 304–310 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The entry of these antibodies into neurons is mainly receptor-mediated but can also occur via bulk endocytosis to some extent.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
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In the paper
“However, two patients withdrew owing to adverse reactions (seizure and viral infection), which might have been treatment-related, and an episode of microhaemorrhage was reported in one patient with a history of this condition.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [241] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01850238 (2015).
- Not checked yetcites [242] Novak, P. et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 16, 123–134 (2017). source
hedgedconditionaln = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Immunization of transgenic tauopathy rats with a vaccine based on this sequence (KLH-linked Tau294–305) elicited tau antibodies that bound to tau in the brain, reduced the levels of pathological tau and improved behaviour, compared with animals that received alum adjuvant only197.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [197] Kontsekova, E., Zilka, N., Kovacech, B., Novak, P. & Novak, M. First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res. Ther. 6, 44 (2014). source
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In the paper
“Adverse effects were limited to inflammation at the injection site, and the treatment did not produce any deleterious immunological responses.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
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In the paper
“This phenomenon can also be seen in cultured cells: even healthy cells can release tau into the culture medium, where it can be endocytosed234,237.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [234] Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).
- Not checked yetcites [237] Croft, C. L. et al. Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death Dis. 8, e2671 (2017). source
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In the paper
“Almost all of the participants (29 of 30) developed an immunoglobulin G response, and no instances of encephalitis or oedema were reported.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Active immunization
What the sources say
- Not checked yetcites [241] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01850238 (2015).
- Not checked yetcites [242] Novak, P. et al. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 16, 123–134 (2017). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In transgenic mice, RG7345 was shown to enter neurons and reduce tau pathology224.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [224] Collin, L. et al. Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer’s disease. Brain 137, 2834–2846 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Early reports from the Alzheimer’s Association International Conference in 2017 showed that the antibody was well tolerated in patients at doses up to 16.8 g, and the antibody was detectable in the CSF256.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [256] Rogers, M. B. Treating tau: finally, clinical candidates are stepping into the ring. Alzforum http://www.alzforum.org/news/conference-coverage/treating-tau-finally-clinical-candidates-are-stepping-ring (2017).
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In the paper
“Preclinical testing showed that this antibody binds to amino acids 235–246 in the proline-rich region of tau, and that the antibody was effective in preventing seeding and spreading of pathological tau261.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
What the sources say
- Not checked yetcites [261] Rogers, M. B. To block tau’s proteopathic spread, antibody must attack its mid-region. Alzforum https://www.alzforum.org/news/conference-coverage/block-taus-proteopathic-spread-antibody-must-attack-its-mid-region (2018).
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In the paper
“In addition, multiple groups have tau antibodies in development, but not yet in clinical trials.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“When added to the media of cultured neurons, these fragments induced hyperactivity and increased Aβ production, and these effects were blocked by the application of an antibody recognizing residues 9–18 of e-tau.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [215] Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015). source
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In the paper
“Furthermore, curcumin is limited by its bioavailability, and has yet to demonstrate efficacy in humans with tauopathy.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Of note, CSF tau levels are increased in AD but not in the other tauopathies57–60, suggesting that extracellular spread of tau pathology is not a prominent feature of non-AD tauopathies.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
What the sources say
- Not checked yetcites [57] Hall, S. et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch. Neurol. 69, 1445–1452 (2012). source
- Not checked yetcites [58] Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations — progress and challenges. Prog. Neurobiol. 95, 636–648 (2011). source
- Not checked yetcites [59] Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016). source
- Not checked yetcites [60] Wagshal, D. et al. Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and progressive supranuclear palsy. J. Neurol. Neurosurg. Psychiatry 86, 244–250 (2015). source
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In the paper
“Infusion of this antibody into the brain in a transgenic mouse model of tauopathy reduced the levels of aggregated and hyperphosphorylated tau, and also improved cognition213.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
What the sources say
- Not checked yetcites [213] Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In AD and PART, the tau aggregates are a mixture of three-repeat and four-repeat tau isoforms, whereas four-repeat sequences dominate in PSP and CBD and three-repeat sequences predominate in Pick disease14,18,19,21.”
§ Tau-targeting therapies for Alzheimer disease > Pathological processes in tauopathies
What the sources say
- Not checked yetcites [14] Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014). source
- Not checked yetcites [18] Arima, K. Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in tauopathies. Neuropathology 26, 475–483 (2006). source
- Not checked yetcites [19] Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989). source
- Not checked yetcites [21] Noble, W., Hanger, D. P., Miller, C. C. & Lovestone, S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol. 4, 83 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, active glycogen synthase kinase-3β (GSK3β)29 and its regulator c-JUN N-terminal kinase (JNK)30 are associated with neurofibrillary pathology and are upregulated in AD.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [29] Tell, V. & Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci. 7, 189 (2013). source
- Not checked yetcites [30] Yarza, R., Vela, S., Solas, M. & Ramirez, M. J. c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front. Pharmacol. 6, 321 (2015).
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“However, hippocampal-sparing and limbic-predominant subtypes are thought to constitute ~25% of AD cases13.”
§ Tau-targeting therapies for Alzheimer disease > Pathological processes in tauopathies
What the sources say
- Not checked yetcites [13] Murray, M. E. et al. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 10, 785–796 (2011). source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Expression of PP2A and its activators is significantly reduced in the brains of individuals with AD compared with age-matched controls, whereas PP2A inhibitors are upregulated34.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [34] Sontag, J. M. & Sontag, E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front. Mol. Neurosci. 7, 16 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, N-glycosylation of tau, which is thought to promote phosphorylation and pathological conformational changes, is increased in AD9,35.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [9] Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat. Med. 2, 871–875 (1996). source
- Not checked yetcites [35] Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, in cell models, soluble oligomeric tau can induce seeding of native tau54,64, and small tau aggregates isolated from patients or animals with AD can induce tau pathology in mice54,64,65.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [64] Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017). source
- Not checked yetcites [65] Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In MCI and AD, the pattern of kinase activation in the mechanistic target of rapamycin (mTOR) pathway is altered69–71 and expression of other key autophagy-related proteins is reduced72 in the brain.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [69] Tramutola, A. et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J. Neurochem. 133, 739–749 (2015). source
- Not checked yetcites [70] Li, X., Alafuzoff, I., Soininen, H., Winblad, B. & Pei, J. J. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J. 272, 4211–4220 (2005). source
- Not checked yetcites [71] Lafay-Chebassier, C. et al. mTOR/p70S6k signalling alteration by Aβ exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J. Neurochem. 94, 215–225 (2005). source
- Not checked yetcites [72] Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Acetylation also contributes to tau pathology by inducing tau cleavage, preventing ubiquitin binding and impeding tau turnover8,35.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Like phosphorylation and acetylation, truncation inhibits the ability of tau to bind to microtubules, and also promotes tau aggregation36,37, mitochondrial dysfunction37 and synaptic deficits39.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Post-translational modifications
What the sources say
- Not checked yetcites [36] Cotman, C. W., Poon, W. W., Rissman, R. A. & Blurton-Jones, M. The role of caspase cleavage of tau in Alzheimer disease neuropathology. J. Neuropathol. Exp. Neurol. 64, 104–112 (2005). source
- Not checked yetcites [37] Guo, T., Noble, W. & Hanger, D. P. Roles of tau protein in health and disease. Acta Neuropathol. 133, 665–704 (2017). source
- Not checked yetcites [39] Jadhav, S. et al. Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front. Cell. Neurosci. 9, 24 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In AD, brain neurons show a reduction in the number and length of microtubules41, reduced levels of acetylated tubulin42,43 (a marker of stable microtubules), and axonal swellings containing vesicles and organelles44.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Cytoskeletal dysfunction
What the sources say
- Not checked yetcites [41] Cash, A. D. et al. Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol. 162, 1623–1627 (2003). source
- Not checked yetcites [42] Hempen, B. & Brion, J. P. Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 964–972 (1996). source
- Not checked yetcites [43] Zhang, F. et al. Posttranslational modifications of α-tubulin in Alzheimer disease. Transl Neurodegener. 4, 9 (2015). source
- Not checked yetcites [44] Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307, 1282–1288 (2005). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Although CSF tau levels are higher in AD than in controls, the levels decrease as the disease progresses, despite the accrual of NFTs56.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [56] Fagan, A. M. et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci. Transl Med. 6, 226ra30 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Neurons containing tangles also have fewer synapses and reduced levels of synaptophysin mRNA compared with tangle-free neurons52,53.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [52] Callahan, L. M., Vaules, W. A. & Coleman, P. D. Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles. J. Neuropathol. Exp. Neurol. 58, 275–287 (1999). source
- Not checked yetcites [53] Ginsberg, S. D., Hemby, S. E., Lee, V. M., Eberwine, J. H. & Trojanowski, J. Q. Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann. Neurol. 48, 77–87 (2000). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligomeric tau has emerged as the probable candidate for the most toxic species in tauopathies, and is present in the brain at early stages of mild cognitive impairment (MCI) and AD54,55,61.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [55] Cárdenas-Aguayo Mdel, C., Gómez-Virgilio, L., DeRosa, S. & Meraz-Ríos, M. A. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem. Neurosci. 5, 1178–1191 (2014). source
- Not checked yetcites [61] Mufson, E. J., Ward, S. & Binder, L. Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer’s disease. Neurodegener. Dis. 13, 151–153 (2014). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Tau oligomers promote toxicity in cell models to a greater extent than filamentous tau, and are linked to neurodegeneration and cognitive phenotypes in vivo54,55”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Tau aggregation
What the sources say
- Not checked yetcites [54] Shafiei, S. S., Guerrero-Munoz, M. J. & Castillo-Carranza, D. L. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front. Aging Neurosci. 9, 83 (2017). source
- Not checked yetcites [55] Cárdenas-Aguayo Mdel, C., Gómez-Virgilio, L., DeRosa, S. & Meraz-Ríos, M. A. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem. Neurosci. 5, 1178–1191 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The drug was well tolerated and the findings support further development134.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [134] Sandhu, P. et al. Pharmacokinetics and pharmacodynamics to support clinical studies of MK-8719: an O-GlcNAcase inhibitor for progressive supranuclear palsy [abstract]. Alzheimers Dement. 12 (Suppl.), P4–036 (2016).
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one. The quote only partly states this claim.
In the paper
“In a recent study129, patients with AD were given very low doses of lithium (300 μg daily) for 15 months. This treatment resulted in a stabilization of cognitive symptoms, whereas placebo-treated patients showed cognitive decline.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [129] Nunes, M. A., Viel, T. A. & Buck, H. S. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr. Alzheimer Res. 10, 104–107 (2013).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In animal models of AD, tideglusib reduces tau phosphorylation, Aβ plaque burden, memory deficits, cell death and astrocytosis118,119.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [118] DaRocha-Souto, B. et al. Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer’s disease. Neurobiol. Dis. 45, 425–437 (2012). source
- Not checked yetcites [119] Sereno, L. et al. A novel GSK-3β inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol. Dis 35, 359–367 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a phase IIa clinical trial in patients with mild to moderate AD, sodium selenate showed some benefits on diffusion MRI but not on other measures, including CSF levels of tau and Aβ, cognition, volumetric MRI and PET imaging109.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [109] Malpas, C. B. et al. A phase IIa randomized control trial of VEL (sodium selenate) in mild–moderate Alzheimer’s disease. J. Alzheimers Dis. 54, 223–232 (2016). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Autophagosomes contain APP, presenilin and γ-secretase, and disruption of autophagosome processing in neurons can lead to increased production of Aβ77, which can in turn further inhibit protein digestion78,79.”
§ Tau-targeting therapies for Alzheimer disease > Targetable pathological events > Protein degradation pathway impairment
What the sources say
- Not checked yetcites [77] Yu, W. H. et al. Macroautophagy — a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 171, 87–98 (2005). source
- Not checked yetcites [78] Lin, C. L. et al. Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity. Exp. Neurol. 275, 84–98 (2016). source
- Not checked yetcites [79] Park, H. et al. Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. Hum. Mol. Genet. 21, 2725–2737 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, the drug has been shown to improve cognition and reduce pathology in Aβ and tauopathy mice, and in rats treated with exogenous Aβ, suggesting its potential utility for treating AD85.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Modulating protein degradation
What the sources say
- Not checked yetcites [85] Gurney, M. E., D’Amato, E. C. & Burgin, A. B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Neurotherapeutics 12, 49–56 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In preclinical testing, epithilone D increased microtubule numbers and reduced the number of axons with abnormal morphology in young157 and aged158 tau transgenic mice.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Microtubule stabilizers
What the sources say
- Not checked yetcites [157] Brunden, K. R. et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci. 30, 13861–13866 (2010). source
- Not checked yetcites [158] Zhang, B. et al. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J. Neurosci. 32, 3601–3611 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In other mouse models of tauopathy, the drug improved cognition, and reduced tau pathology and tau-related changes in microtubule dynamics159.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Microtubule stabilizers
What the sources say
- Not checked yetcites [159] Barten, D. M. et al. Hyperdynamic microtubules, cognitive deficits, and pathology are improved in tau transgenic mice with low doses of the microtubule-stabilizing agent BMS-241027. J. Neurosci. 32, 7137–7145 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As tau is not only directly toxic to cells but is also a mediator of Aβ toxicity88, reducing tau levels would seem to be a logical therapeutic approach for AD.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Reducing tau expression
What the sources say
- Not checked yetcites [88] Ittner, L. M. & Götz, J. Amyloid-β and tau — a toxic pas de deux in Alzheimer’s disease. Nat. Rev. Neurosci. 12, 65–72 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In patients with MCI, lithium treatment significantly reduced phospho-tau levels in CSF and improved cognitive performance127,128.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [127] Forlenza, O. V., De-Paula, V. J. & Diniz, B. S. Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014). source
- Not checked yetcites [128] Forlenza, O. V. et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br. J. Psychiatry 198, 351–356 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In a larger phase II study, tideglusib treatment was associated with significant cognitive improvement and a reduction in CSF levels of β-secretase in a subgroup of patients with mild AD122. However, when the entire study cohort was analysed, tideglusib was found to be well tolerated but produced no significant improvements122.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [122] Lovestone, S. et al. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis. 45, 75–88 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In mouse models, tau knockout has few adverse effects89, presumably because other microtubule-associated proteins can, to a large extent, compensate for loss of the tau protein.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Reducing tau expression
What the sources say
- Not checked yetcites [89] Ke, Y. D. et al. Lessons from tau-deficient mice. Int. J. Alzheimers Dis. 2012, 873270 (2012).
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This agent was effective at reducing tau pathology and improving cognitive phenotypes in transgenic mouse models of tauopathy137.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Tau aggregation inhibitors
What the sources say
- Not checked yetcites [137] Panza, F. et al. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. Biomed. Res. Int. 2016, 3245935 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In preclinical testing, salsalate reduced p300 HAT activity, leading to reduced tau pathology, preserved hippocampal volume and improved cognition in transgenic mice.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [132] Min, S. W. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 21, 1154–1162 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In patients with moderate to severe AD, memantine promoted small short-term improvements in cognition99,100, and it also seemed to provide modest benefits in FTD101.”
§ Tau-targeting therapies for Alzheimer disease > Tau-targeting drugs > Targeting tau protein modifications
What the sources say
- Not checked yetcites [99] Jiang, J. & Jiang, H. Efficacy and adverse effects of memantine treatment for Alzheimer’s disease from randomized controlled trials. Neurol. Sci. 36, 1633–1641 (2015). source
- Not checked yetcites [100] Matsunaga, S., Kishi, T. & Iwata, N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS ONE 10, e0123289 (2015). source
- Not checked yetcites [101] Kishi, T., Matsunaga, S. & Iwata, N. Memantine for the treatment of frontotemporal dementia: a meta-analysis. Neuropsychiatr. Dis. Treat. 11, 2883–2885 (2015). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“To date, Aβ immunotherapies have been largely unsuccessful, possibly because they were only administered once the symptoms of AD had become apparent173–178.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
What the sources say
- Not checked yetcites [173] Lobello, K., Ryan, J. M., Liu, E., Rippon, G. & Black, R. Targeting beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer’s disease. Int. J. Alzheimers Dis. 2012, 628070 (2012).
- Not checked yetcites [174] Valera, E., Spencer, B. & Masliah, E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics 13, 179–189 (2016). source
- Not checked yetcites [175] Abushouk, A. I. et al. Bapineuzumab for mild to moderate Alzheimer’s disease: a meta-analysis of randomized controlled trials. BMC Neurol. 17, 66 (2017). source
- Not checked yetcites [176] Penninkilampi, R., Brothers, H. M. & Eslick, G. D. Safety and efficacy of anti-amyloid-β immunotherapy in Alzheimer’s disease: a systematic review and meta-analysis. J. Neuroimmune Pharmacol. 12, 194–203 (2017). source
- Not checked yetcites [177] Wisniewski, T. & Drummond, E. Developing therapeutic vaccines against Alzheimer’s disease. Expert Rev. Vaccines 15, 401–415 (2016). source
- Not checked yetcites [178] Panza, F., Solfrizzi, V., Imbimbo, B. P. & Logroscino, G. Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return? Expert Opin. Biol. Ther. 14, 1465–1476 (2014). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The ability of the antibody to enter neurons was not assessed.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, both strategies have been well tolerated and have not produced the types of adverse effects that led to trial termination or dosing adjustments in some of the Aβ immunotherapy trials.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Adding to the complexity is the fact that many of the compounds under investigation might exert effects through more than one pathway.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On numerous occasions, preclinical success in animal models has failed to translate into benefits in humans.”
§ Tau-targeting therapies for Alzheimer disease > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Various factors govern the efficacy of anti-tau antibodies, the most important of which are probably the epitope (normal or primarily pathological) and the site of action (extracellular and intracellular, or extracellular only).”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, anti-tau antibodies that primarily work extracellularly should probably target amino acids 150–250, and might only work in AD.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Future prospects
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The pathogenesis of tauopathies is likely to differ.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“As an early-stage trial, the number of participants is insufficient for efficacy assessment.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies > Passive immunization
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Attempts to alter the disease course of AD by removing Aβ or reducing its production have been largely unsuccessful.
“Unfortunately, attempts to alter the disease course by removing Aβ or reducing its production have been largely unsuccessful.”
The paper relies on this without support.
Aβ is not a confounding variable in the non-AD tauopathies.
“Aβ is not a confounding variable in the non-AD tauopathies”
The paper relies on this without support.
Elicitation of antibodies against a native protein carries the risk of adverse immune reactions and detrimental targeting of the normal protein.
“However, elicitation of antibodies against a native protein always carries the risk of adverse immune reactions and detrimental targeting of the normal protein.”
The paper relies on this without support.
The pathogenesis of tauopathies is likely to differ.
“Although the pathological epitopes seen in AD are common to most if not all of the tauopathies, the pathogenesis of these conditions is likely to differ.”
The paper relies on this without support.
Solanezumab did not alter tau levels in treated individuals in any of the trials.
“Likewise, solanezumab did not alter tau levels in treated individuals in any of the trials.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“At present, due to the toxicity or lack of efficacy of other anti-tau therapies, most of the tau targeted therapies undergoing clinical trials are immune-based therapies.531”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [531]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Clinical trials of methylene blue-derived tau inhibitors in AD have generally yielded disappointing results [47–49].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“At present, multiple clinical trials based on tau active and passive immunization are ongoing since the tests in the animal models have yielded promising results.531”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [531]
The cited source says what the claim attributes to it.
In the citing paper
“The passive transfer of anti-tau antibodies has also been shown to be an effective method, since it was reported that tau can be secreted into the extracellular space,535 and some antibodies even can enter neurons.531”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [531]
In the citing paper
“In animal models, case in point, antibodies that bind selectively to phosphorylated tau have shown promise in lowering tau pathology.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [95]
In the citing paper
“But a lot of these methods have had difficulties in the clinic, frequently because of problems with toxicity or ineffectiveness [95,98].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [95]
In the citing paper
“Research has indicated that tau pathology has a stronger correlation with cognitive deficits than Aβ plaques, indicating that treatment benefits from targeting tau may outweigh those from concentrating only on amyloid clearance [94,95].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [95]
In the citing paper
“Select tau immunotherapies currently employed in AD trials have previously failed to demonstrate any effect on disease progression in the primary tauopathy progressive supranuclear palsy (PSP), fueling reservations about their utility in other neurodegenerative disorders [49].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [49]
In the citing paper
“One of the major bottlenecks in developing effective therapies for tauopathies resides in the fact that molecular mechanisms leading to neuronal toxicity and death are still not entirely understood”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Congdon and Sigurdsson, 2018
Citations
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Research works printed but not linked: 6
- Fagan, T. In first phase 3 trial, the tau drug LMTM did not work. Period. Alzforum http://www.alzforum.org/news/conference-coverage/first-phase-3-trial-tau-drug-lmtm-did-not-work-period#show-more (2016).
- Fagan, T. Tau inhibitor fails again — subgroup analysis irks clinicians at CTAD. Alzforum http://www.alzforum.org/news/conference-coverage/tau-inhibitor-fails-again-subgroup-analysis-irks-clinicians-ctad (2016).
- [No authors listed.] Biogen licenses phase 2 anti-tau antibody from Bristol-Myers Squibb. Biogen http://media.biogen.com/press-release/corporate/biogen-licenses-phase-2-anti-tau-antibody-bristol-myers-squibb (2017).
- West, T. et al. Safety, tolerability and pharmacokinetics of ABBV-8E12, a humanized anti-tau monoclonal antibody, in a Phase I, single ascending dose, placebo-controlled study in subjects with progressive supranuclear palsy. J. Prev. Alzheimers Dis. 3, 285 (2016).
- Rogers, M. B. Treating tau: finally, clinical candidates are stepping into the ring. Alzforum http://www.alzforum.org/news/conference-coverage/treating-tau-finally-clinical-candidates-are-stepping-ring (2017).
- Rogers, M. B. To block tau’s proteopathic spread, antibody must attack its mid-region. Alzforum https://www.alzforum.org/news/conference-coverage/block-taus-proteopathic-spread-antibody-must-attack-its-mid-region (2018).
Cited by
Sorted by citations
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“At present, due to the toxicity or lack of efficacy of other anti-tau therapies, most of the tau targeted therapies undergoing clinical trials are immunebased therapies.(531) Sigurdsson’s group was the first to report successful tau targeted therapy based on active and passive immunization against tau, which reduced p…”
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Metadata
- Authors
- Congdon, E. E., & Sigurdsson, E. M.
- Affiliations
- New York University (US)
- Corresponding author
- Sigurdsson, Einar M.
- Venue
- Nature Reviews Neurology
- Published
- 2018-06-12
- Volume
- 14
- Issue
- 7
- Pages
- 399-415
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC6463489
- OpenAlex
- W2808028315
- Semantic Scholar
- 716fddb15717f7605097dd659e8360bee46935ee
- Cited by
- 1,113
- References
- 235
- Citations by year
- 2026: 70 · 2025: 134 · 2024: 154 · 2023: 141 · 2022: 179 · 2021: 168 · 2020: 161 · 2019: 82 · 2018: 22
- FWCI
- 14.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- H. Lundbeck A/S
- National Institutes of Health
- National Institute on Aging (R01AG032611)
- National Institute of Neurological Disorders and Stroke (R01NS077239)
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, tau protein, tau immunotherapy, amyloid-beta, neurofibrillary tangles, tau aggregation, kinase inhibition, microtubule stabilization, clinical trial failure
- MeSH terms
- Alzheimer Disease, Animals, Humans, tau Proteins
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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