The DOI matches its Crossref record; 232 of the 235 references it cites were found in a registry or an index; 12 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
100 Not checked yet · 20 Own interpretation · 9 No basis given · 2 Supported so far · 2 Partly supported · 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)
hedged- Asserted: passes — The authors put it forward as true.
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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)
plain- Asserted: passes — The authors put it forward as true.
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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)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Supported
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)
hedgedconditional- 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
“Some data indicate that Aβ immunotherapy has noteworthy but modest effects on tau pathology.”
§ Tau-targeting therapies for Alzheimer disease > Tau immunotherapies
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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).
plain- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 57
- Probably not a substantial claim. 7
- The quote only partly states this claim. 1
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.
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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.
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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.
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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.
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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.
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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
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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
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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 [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
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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
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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
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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
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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
“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
- 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 [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
“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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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
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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
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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).
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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
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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
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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
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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
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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).
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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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- 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 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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- 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
“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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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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It may state two separate claims as one.
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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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
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.
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- 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.
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- 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.
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- 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.
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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.
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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.
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- 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.
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- 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.
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- 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.
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- 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.
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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.
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- 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.
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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
Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
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Items 501–600 of 1,000
Nishioka, K., Imai, Y., Yoshino, H., Li, Y., Funayama, M., & Hattori, N. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.764917 · Cited by 17
“These would include oligonucleotide therapeutics (170), antibody therapies against α-synuclein and tau (171, 172), or replacement therapies of induced pluripotent stem cells (173).”
BackgroundKimura, T., Ono, M., Seki, C., Sampei, K., Shimojo, M., Kawamura, K., Zhang, M., Sahara, N., Takado, Y., & Higuchi, M. (2022) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-022-05898-3 · Cited by 16
“The present study is aimed at establishing a non-clinical neuroimaging platform for the precise investigation of tau pathologies and their correlation with neuronal loss in Tg model mice towards the elucidation of tau neurotoxicity and examination of potential disease-modifying therapies represented by the latest anti…”
BackgroundCastro, T. G., Ferreira, T., Matamá, T., Munteanu, F., & Cavaco-Paulo, A. M. (2022) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2022.130276 · Cited by 18
Recent advances of PROTACs technology in neurodegenerative diseases
Wang, C., Zhang, Y., Yang, S., & Xing, D. (2023) · Arabian Journal of Chemistry · doi:10.1016/j.arabjc.2023.105015 · Cited by 17
Fang, L., Jiao, B., Liu, X., Wang, Z., Yuan, P., Zhou, H., Xiao, X., Cao, L., Guo, J., Tang, B., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.11.018 · Cited by 17
Glioblastoma and its treatment are associated with extensive accelerated brain aging
Ainslie, A. P., Klaver, M., Voshart, D. C., Gerrits, E., den Dunnen, W. F. A., Eggen, B. J. L., Bergink, S., & Barazzuol, L. (2024) · Aging Cell · doi:10.1111/acel.14066 · Cited by 17
“The results of this study provide the basis for further testing existing or novel AD therapies, including therapeutic strategies targeting p-Tau aggregation (Congdon & Sigurdsson, 2018 ), in brain tumor patients thereby improving their quality of life.”
BackgroundVollhardt, A., Frölich, L., Stockbauer, A., Danek, A., Schmitz, C., & Wahl, A.-S. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106845 · Cited by 18
“…has been challenging for VaD, due to the heterogeneity of the underlying pathology (Iadecola, 2013), but also for AD drug development, especially targeting A ß accumulation and tau pathology has been demanding (Congdon and Sigurdsson, 2018; Weller and Budson, 2018; Pinheiro and Faustino, 2019).”
Pharmakologische Therapie der Alzheimer-Demenz
Müller, P., Fendt, M., & Müller, N. (2019) · Der Internist · doi:10.1007/s00108-019-0625-4 · Cited by 17
Myocardial Infarction Predisposes Neurodegenerative Diseases
Zhang, W., & Luo, P. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191225 · Cited by 17
“The amyloid cascade hypothesis has dominated the field of AD research for a very long period until its failure in clinical trials [13].”
Pourhamzeh, M., Joghataei, M. T., Mehrabi, S., Ahadi, R., Hojjati, S. M. M., Fazli, N., Nabavi, S. M., Pakdaman, H., & Shahpasand, K. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00906-2 · Cited by 18
RetractedRoda, A. R., Montoliu‐Gaya, L., Serra-Mir, G., & Villegas, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186630 · Cited by 17
Tatiparti, K., Sau, S., Rauf, M. A., & Iyer, A. K. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.09.025 · Cited by 16
Nguyen, T. T., Vo, T. K., & Vo, G. V. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-55035-6_13 · Cited by 18
Podvin, S., Jones, A. C., Liu, Q., Aulston, B. D., Mosier, C., Ames, J., Winston, C. N., Lietz, C. B., Jiang, Z., O’Donoghue, A. J., et al. (2021) · ACS Omega · doi:10.1021/acsomega.1c00660 · Cited by 16
Yao, M., Rosario, E. R., Soper, J. C., & Pike, C. J. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.06.034 · Cited by 20
Considerations for future tau-targeted therapeutics: can they deliver?
Noble, W. J., Jiménez-Sánchez, M., Perez‐Nievas, B. G., & Hanger, D. P. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1685977 · Cited by 16
Recent Advances in Antibody Therapy for Alzheimer’s Disease: Focus on Bispecific Antibodies
Yang, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136271 · Cited by 19
Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer’s disease
Vanya, Kumari, S., Bagri, K., & Deshmukh, R. R. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.10.050 · Cited by 18
Moscoso, A., Grothe, M. J., Schöll, M., & Initiative, A. D. N. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05195-5 · Cited by 16
A Pathway-Specific Polygenic Risk Score Is Associated with Tau Pathology and Cognitive Decline
Sun, Y., Wang, M., Zhao, Y., Hu, K., Liu, Y., Liu, B., & Initiative, A. D. N. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215163 · Cited by 17
“Previous neuropathologic studies suggested that aberrant hyperphosphorylation of tau is the result of the upregulation of tau kinases, leading to microtubule disassembly [10, 11].”
Recent studies of atomic‐resolution structures of tau protein and structure‐based inhibitors
Zhu, L., & Qian, Z. (2021) · Quantitative Biology · doi:10.15302/j-qb-021-0271 · Cited by 16
Liu, R., Yang, J., Qiu, X., Ji, W., Shen, J., Li, Y., Lü, Z., Wu, Y., Wang, W., Wang, J., et al. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202101748 · Cited by 19
Combination Therapy for the Treatment of Alzheimer’s Disease: Recent Progress and Future Prospects
Shirbhate, E., Patel, V. K., Tiwari, P., Kore, R., Veerasamy, R., Mishra, A., & Rajak, H. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026622666220907114443 · Cited by 18
Mi, Y., Xu, J., Shi, R., Meng, Q., Xu, L., Liu, Y., Guo, T., Zhou, D., Liu, J., Li, W., et al. (2022) · Food & Function · doi:10.1039/d2fo01476a · Cited by 18
Luo, Z., Li, S., Zhang, Y., Yin, F., Luo, H., Chen, X., Cui, N., Wan, S., Li, X., Kong, L., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115415 · Cited by 16
Gul, S., Attaullah, S., Alsugoor, M. H., Bawazeer, S., Shah, S. A., Khan, S., Salahuddin, H. S., & Ullah, M. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e16930 · Cited by 17
“2 hallmarks for the diagnosis of Alzheimer disease include the disposition of plaques of amyloid beta, glial responses, neurofibrillary tangles of Tau protein and neuronal and synaptic loss [3,4,5,6].”
BackgroundJain, U., Johari, S., & Srivastava, P. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03671-7 · Cited by 16
“Being a microtubule-associated protein, it also stabilizes neuronal microtubules under normal conditions [44, 45].”
Peptide-based inhibitors and nanoparticles: Emerging therapeutics for Alzheimer’s disease
Mojarad-Jabali, S., & Roh, K. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.125055 · Cited by 17
Chakravarthy, M., Chen, S., Wang, T., & Veedu, R. N. (2020) · Genes · doi:10.3390/genes11060667 · Cited by 16
“Furthermore, it has been hypothesized that the reduction in tau monomers may result in depolymerization of the paired helical filaments to maintain equilibrium [9].”
BackgroundInfluentialTrait anxiety, a personality risk factor associated with Alzheimer’s Disease
Li, S., Wang, C., Wang, W., & Tan, J. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110124 · Cited by 21
Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267–312 Monomer
Chatterjee, S., Salimi, A., & Lee, J. Y. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00587 · Cited by 16
Potential new therapeutic target for Alzheimer's disease: Glucagon‐like peptide‐1
Liu, X., Zhang, N., Zhang, S., & Xu, P. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15502 · Cited by 16
“2.3.2 | Tau phosphorylation Another major pathologic feature of AD is the intraneuronal NFTs formed by misfolding and aggregation of the hyperphosphorylated tau protein (Congdon & Sigurdsson, 2018; Wharton et al., 2016).”
BackgroundInfluentialPositron Emission Tomography in Animal Models of Tauopathies
Cao, L., Kong, Y., Ji, B., Ren, Y., Guan, Y., & Ni, R. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.761913 · Cited by 14
Morderer, D., Wren, M. C., Liu, F., Kouri, N., Maistrenko, A., Khalil, B., Pobitzer, N., Salemi, M., Phinney, B. S., Bu, G., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00817-0 · Cited by 21
“…of dissecting the composition of disease-specific and shared tau-associated proteins for the development of therapeutic strategies that target mechanisms of tau aggregation, as well as development of biomarkers for differential diagnosis and disease-specific early detection of tauopathies [28–34].”
Shukla, M., Wongchitrat, P., & Govitrapong, P. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03530-2 · Cited by 12
“Although several possible therapeutic targets for restraining the propagation of tau pathology and preventing neuronal damage have been identified with many undergoing clinical trials of drugs which would restrict the development of tangle formation [75], but the toxicity and efficacy criterion becomes an essential co…”
BackgroundGu, L., Cai, N., Li, M., Bi, D., Yao, L., Fang, W., Wu, Y. L., Hu, Z., Liu, Q., Lin, Z., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.892558 · Cited by 15
“It has been reported that decreasing Tau hyperphosphorylation has been considered as an approach to improve cognition (31).”
BackgroundWang, B., Zhong, X., Fields, L. G., Lu, H., Zhu, Z., & Li, L. (2023) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.2c00332 · Cited by 15
Tau trajectory in Alzheimer’s disease: Evidence from the connectome-based computational models
Bitra, V. R., Challa, S. R., Adiukwu, P. C., & Rapaka, D. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110777 · Cited by 15
“Phosphorylation can occur before cleavage at Asp421 (Congdon and Sigurdsson, 2018), making the tau susceptible to accretion; however, phosphorylation at Ser422 prevents this break-down procedure.”
InfluentialLing, L., Luo, Y., Kang, D., Yang, F., Meng, D., Wang, J., Liu, R., Wang, X., & Li, H. (2023) · Aging · doi:10.18632/aging.205295 · Cited by 21
“Several drugs targeting Aβ and phosphorylation of tau were discontinued due to poor efficacy [44, 45].”
BackgroundDetecting the effect of genetic diversity on brain composition in an Alzheimer’s disease mouse model
Gurdon, B., Yates, S. C., Csucs, G., Groeneboom, N. E., Hadad, N., Telpoukhovskaia, M., Ouellette, A., Ouellette, T., O’Connell, K. M. S., Singh, S., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06242-1 · Cited by 15
Silva, P., & Vauzour, D. (2018) · Beverages · doi:10.3390/beverages4040096 · Cited by 15
“Damaged neurons are the ones with Tau-positive NFTs, which extend to the dendrites, and can be released and taken up by healthy neurons, triggering tau damage in the uptaking cell (Figure 2) [21].”
BackgroundThe Israel Registry for Alzheimer’s Prevention (IRAP) Study: Design and Baseline Characteristics
Ravona‐Springer, R., Sharvit‐Ginon, I., Ganmore, I., Greenbaum, L., Bendlin, B. B., Sternberg, S. A., Livny, A., Domachevsky, L., Sandler, I., Ben‐Haim, S., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200623 · Cited by 16
“Numerous compounds, including those targeting amyloid plaques [8, 9] and neurofibrillary tangles [10], failed in clinical trials in symptomatic as well as in asymptomatic patients [11].”
Chatterjee, S., Salimi, A., & Lee, J. Y. (2021) · Physical Chemistry Chemical Physics · doi:10.1039/d1cp00105a · Cited by 15
Fortin, J. S., Shimanaka, K., Saraswati, A. P., Liu, M., Wang, K., Hagar, H. C., Maity, S., Ganegamage, S. K., Ellsworth, E. L., Counts, S., et al. (2022) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2022.133574 · Cited by 17
Zhu, B., Parsons, T., Stensen, W., Svendsen, J. S. M., Fugelli, A., & Hodge, J. J. L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.881385 · Cited by 18
“Only 5% of the causes of AD are thought to be genetic, making it difficult to predict who will develop the disease or not, with diagnosis only usually possible after extensive and irreversible neurodegeneration has occurred frustrating attempts at early intervention and development of effective treatments (Querfurth a…”
BackgroundDoering, S., McCullough, A. A., Gordon, B. A., Chen, C. D., McKay, N. S., Hobbs, D. A., Keefe, S., Flores, S. E., Scott, J., Smith, H. D., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105080 · Cited by 19
“57 With the surge of these trials, evaluating both TI and TSS may provide additional insight into the success of tau-targeting drugs in reducing or slowing tau progression, particularly in the preclinical stage at which the metrics show the largest divergence.”
BackgroundEmerging Molecular Targets in Neurodegenerative Disorders: New Avenues for Therapeutic Intervention
Eroglu, E., & HARMANCI, N. (2025) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.70107 · Cited by 16
“Similarly, tau-targeting therapies—ranging from small-molecule aggregation inhibitors and kinase modulators (targeting GSK-3 β and CDK5) to anti-tau immunotherapies—have thus far failed to show meaningful cognitive or functional improvements in patients with ad or related tauopathies [19, 20].”
ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease
Shinohara, M., Hirokawa, J., Shimodaira, A., Tashiro, Y., Suzuki, K., Gheni, G., Fukumori, A., Matsubara, T., Morishima, M., Saito, Y., et al. (2021) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlab047 · Cited by 16
Squitti, R., Ventriglia, M., Granzotto, A., Sensi, S. L., & Rongioletti, M. C. A. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666211022085755 · Cited by 14
Secondary Prevention of Dementia: Combining Risk Factors and Scalable Screening Technology
Ojakäär, T., & Koychev, I. G. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.772836 · Cited by 12
“Early tau targeting therapies have primarily focussed on either inhibition of kinases, tau aggregation or stabilization of microtubules, however, trials have been mostly unsuccessful due to toxicity and lack of efficacy (119).”
BackgroundMicrotubule Integrity Is Associated with the Functional Activity of Mitochondria in HEK293
Cho, M. J., Kim, Y. J., Kim, Y. J., Kim, Y. S., & Lee, J. H. (2021) · Cells · doi:10.3390/cells10123600 · Cited by 15
“Tau is a biomarker of dementia and a therapeutic target protein for neurodegenerative disorders [9].”
BackgroundCarriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system
Diks, A. M., Teodosio, C., de Mooij, B., Groenland, R. J., Naber, B. A. E., de Laat, I. F., Vloemans, S. A., Rohde, S., de Jonge, M. I., Lorenz, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00604-9 · Cited by 14
Davidowitz, E. J., Lopez, P., Jimenez, H. T., Adrien, L. R., Davies, P., & Moe, J. G. (2023) · PLoS ONE · doi:10.1371/journal.pone.0286523 · Cited by 13
Targeting the molecular web of Alzheimer’s disease: unveiling pathways for effective pharmacotherapy
Jadhav, D., Saraswat, N., Vyawahare, N. S., & Shirode, D. S. (2024) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-023-00775-8 · Cited by 17
“Tubulin associated protein (TAU) is crucial for the upkeep of neuronal stability and homeostasis, therefore its hyper phosphorylation triggers a path of events that results in neuronal death [64].”
BackgroundSofińska, K., Seweryn, S., Skirlińska‐Nosek, K., Barbasz, J., & Lipiec, E. W. (2024) · Nanoscale · doi:10.1039/d3nr06365h · Cited by 17
McArthur, N., Kang, B., Moctezuma, F. G. R., Shaikh, A. T., Loeffler, K., Bhatt, N. N., Kidd, M., Zupancic, J. M., Desai, A. A., Djeddar, N., et al. (2024) · Biotechnology Progress · doi:10.1002/btpr.3463 · Cited by 13
“11 These post-translational modifications affect the ability of tau to bind to microtubules, and soluble, hyperphosphorylated tau misfolds and aggregates intracellularly.”
Zhu, Z., Zhong, X., Wang, B., Lu, H., & Li, L. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.4c00182 · Cited by 15
Soltan, O. M., Abdelrahman, K. S., Bass, A. K. A., Takizawa, K., Narumi, A., & Konno, H. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.107651 · Cited by 14
Kardam, S., Ambasta, R. K., & Kumar, P. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102465 · Cited by 17
Fu, W., Chen, M., Wang, K., Chen, Y., Cui, Y., Xie, Y., Lei, Z., Hu, W., Sun, G., Huang, G., et al. (2025) · Cell Research · doi:10.1038/s41422-024-01016-0 · Cited by 17
Epigenetic Control of CDK5 Promoter Regulates Diabetes-Associated Development of Alzheimer’s Disease
Cai, H., Fan, Z., Tian, T., Zhao, C.-C., & Ge, Z.-M. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190227 · Cited by 13
“A (cid:2) and tau protein comprise the pathological plaquesandtanglesseenintheAD-brain[2].”
InfluentialYang, S., Wang, L., Xie, Z., Zeng, Y., Xiong, Q., Pei, T., Wei, D., & Cheng, W. (2022) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2022/9475703 · Cited by 15
“Formed by aggregation of Aβ monomer and hyperphosphorylation of microtubule-associated protein Tau (p-Tau), Aβ plaques and neurofibrillary tangles (NFTs) were considered to be critical biomarkers in AD brains [17].”
BackgroundDai, D., Tropea, T. F., Robinson, J. L., Suh, E. R., Hurtig, H. I., Weintraub, D. A., Deerlin, V. M. V., Lee, E. B., Trojanowski, J. Q., & Chen‐Plotkin, A. S. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02199-7 · Cited by 14
Wu, X., Su, D., Xu, J., Ge, G., Zhang, Y., Wu, B., Hu, K., Ren, J., & Yang, H. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c01158 · Cited by 15
Gou, J., Liang, S., Cheng, W., Wu, S., Ye, Z., Ma, Y., Yin, Y., & Wang, H. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.07.022 · Cited by 13
Nacre extract from pearl oyster attenuates amyloid beta-induced memory impairment
Yotsuya, Y., & Hasegawa, Y. (2022) · Journal of Natural Medicines · doi:10.1007/s11418-021-01598-8 · Cited by 14
“AD is characterized by deposits of amyloid β (Aβ) peptide and the accumulation of hyperphosphorylated tau [3] in the brain.”
BackgroundDutta, B. J., Singh, S., Seksaria, S., Gupta, G. D., Bodakhe, S. H., & Singh, A. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115071 · Cited by 15
A seeding-based neuronal model of tau aggregation for use in drug discovery
Amorim, I. S., Challal, S., Cistarelli, L., Dorval, T., Abjean, L., Touzard, M., Arbez, N., François, A., Panayi, F., Jeggo, R., et al. (2023) · PLoS ONE · doi:10.1371/journal.pone.0283941 · Cited by 14
“Strategies to prevent the formation of tau inclusions Having established the conditions necessary to induce the formation of tau inclusions in hTau primary neurons, we tested how the model responded to molecules aimed at preventing tau aggregation, as these are the focus of many therapeutic approaches for Tauopathies.”
BackgroundInfluentialSingle-domain antibody-based protein degrader for synucleinopathies
Jiang, Y., Lin, Y., Tetlow, A. M., Pan, R., Ji, C., Kong, X., Congdon, E. E., & Sigurdsson, E. M. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00730-y · Cited by 14
“We and others have shown that antibodies can target proteinopathies both intra-and extracellularly ( 27, 38-45 ).”
Self-citationReich, N., Allsop, D., Parkin, E. T., & Dawson, N. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18477 · Cited by 14
FGFR3 drives Aβ-induced tau uptake
Kim, D. K., Suh, K. Y., Park, J., Lee, S., Han, J., Chang, S., Kim, Y., & Mook‐Jung, I. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01274-3 · Cited by 14
Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions
Vashisth, K., Sharma, S., Ghosh, S., Babu, M. A., Ghosh, S., Iqbal, D., Kamal, M., Almutary, A. G., Jha, S. K., Ojha, S. K., et al. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230603 · Cited by 13
“Immunotherapy that targets tau protein has been proven in several preclinical studies to reduce tau pathology and enhance cognitive performance in animal models of AD [116, 117].”
Nagori, K., Nakhate, K. T., Yadav, D. K., Thakur, A., Ajazuddin, M., & Pradhan, M. (2024) · Inorganic Chemistry Communications · doi:10.1016/j.inoche.2024.113604 · Cited by 16
Nanopipettes as a Potential Diagnostic Tool for Selective Nanopore Detection of Biomolecules
Kuanaeva, R. M., Vaneev, A. N., Gorelkin, P. V., & Erofeev, A. S. (2024) · Biosensors · doi:10.3390/bios14120627 · Cited by 15
Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies
Uliassi, E., Bolognesi, M. L., & Milelli, A. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00733 · Cited by 13
Diabetes-Induced H3K9 Hyperacetylation Promotes Development of Alzheimer’s Disease Through CDK5
Cai, H., Fan, Z., Tian, T., Li, Z.-C., Zhao, C.-C., Guo, W., & Ge, Z.-M. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200163 · Cited by 13
“Both increased deposition of extracellular senile plaques by amyloid-(cid:2) peptide aggregates (A (cid:2) ) and formation of intraneuronal neurofibrillary tangles by hyperphosphorylated tau (p-Tau) are featured pathological changes in Alzheimer’s disease (AD) [1, 2].”
Yang, S., Shi, H., Zeng, P. H., Xia, J., Wang, P., & Li, L. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153624 · Cited by 13
Harding, A., Kanagasingam, S., Welbury, R. R., & Singhrao, S. K. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-96881-6_13 · Cited by 14
Liu, H., Zhang, Y., Hu, Y., Zhang, H., Wang, T., Han, Z., Gao, S., Wang, L., & Liu, G. (2021) · Genes & Nutrition · doi:10.1186/s12263-021-00700-9 · Cited by 15
“Introduction Alzheimer’s disease (AD) is the most common neurodegenerative disease, which is characterized by extracellular deposition of amyloid plaques mainly composed of βamyloid protein (Aβ) [1].”
BackgroundExploring the zinc-related transcriptional landscape in Alzheimer’s disease
Shippy, D. C., & Ulland, T. K. (2022) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2022.06.002 · Cited by 15
“To date, many of the therapeutic agents developed for AD have focused on amyloid and tau reduction (Congdon and Sigurdsson, 2018; Pinheiro and Faustino, 2019).”
BackgroundGregory, S., Saunders, S., & Ritchie, C. W. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(22)00219-7 · Cited by 16
“40,44,45 Again, trials of interventions targeting tau have mostly used cognition as a primary outcome, with biomarkers included as secondary or exploratory outcomes.”
BackgroundProbiotic supplement as a promising strategy in early tau pathology prevention: Focusing on GSK-3β?
Flynn, C. M., & Yuan, Q. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1159314 · Cited by 15
“Concerns regarding GSK-3β as a ubiquitously expressed kinase, involved in several key cellular biological processes have been raised (Congdon and Sigurdsson, 2018).”
BackgroundPeptide Interference with APP and Tau Association: Relevance to Alzheimer’s Disease Amelioration
Maron, R., Armony, G., Tsoory, M., Wilchek, M., Frenkel, D., & Arnon, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093270 · Cited by 13
“predicted and used by us, other peptides of the APP and Tau proteins could also be effective to ameliorate amyloid pathology, as described in [31,32].”
MethodInteractions with tau’s microtubule-binding repeats modulate amyloid-β aggregation and toxicity
Kim, M., Lin, Y., Nam, E., Kang, D. M., Lim, S., Kim, Y. K., Lee, Y., & Lim, M. H. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01987-0 · Cited by 15
“Under pathological conditions, tau undergoes aberrant posttranslational modifications that result in the detachment from microtubules and the subsequent aggregation of tau, leading to microtubule destabilization 5,6 .”
Ferrari, I., Limiti, E., Giannitelli, S. M., Trombetta, M., Rainer, A., D’Amelio, M., Barbera, L. L., & Gori, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199478 · Cited by 15
“Over time, there is a progressive loss of neurons, particularly in limbic structures, which results in brain atrophy [4–6].”
AMPKα2 signals amino acid insufficiency to inhibit protein synthesis
Mao, Y.-Z., Cui, M., Jiang, Y., Yu, H., Wang, M., Li, G., Zhang, H., Zhao, C., Shen, Y., An, Y., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.09.004 · Cited by 13
Ke, J., Ding, J., Xu, Y., Yu, C., Hong, Y., Li, S., Meng, T., Yuan, P., Yuan, H., & Hu, F. (2025) · Biomaterials Science · doi:10.1039/d5bm01080b · Cited by 17
An Interactive Review on the Role of Tocotrienols in the Neurodegenerative Disorders
Naomi, R., Shafie, N. H., Kaniappan, P., & Bahari, H. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.754086 · Cited by 14
“Alzheimer’s Disease AD is a form of dementia characterized by deposition of neurofibrillary tangles and amyloid plaques in the brain which resulted in loss of neurons and synapses (21).”
BackgroundWu, S., Yin, Y., & Du, L. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114144 · Cited by 15
The effect of lipid composition on the dynamics of tau fibrils
Chowdhury, U. D., Paul, A., & Bhargava, B. L. (2022) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26401 · Cited by 12
“Research on AD was majorly focused on Aβ peptides but due to failures of Aβ targeting treatments in clinical trials, tau proteins are getting the attention of researchers.(4) A total of six tau protein isoforms are expressed in AD brain, ranging from 352 to 441 amino acids.”
BackgroundXu, Y., Jiang, H., Zhu, B., Cao, M., Feng, T., Sun, Z., Du, G., & Zhao, Z. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14238 · Cited by 11
Small molecules targeting molecular chaperones for tau regulation: Achievements and challenges
He, C., Gu, J., Wang, D., Wang, K., Wang, Y., You, Q., & Wang, L. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115859 · Cited by 12
Zadrożny, M., Drapich, P., Gąsiorowska, A., Niewiadomski, W., Harrington, C. R., Wischik, C. M., Riedel, G., & Niewiadomska, G. (2024) · Cells · doi:10.3390/cells13070642 · Cited by 13
“The reversal of tau aggregation, particularly in basal forebrain cholinergic neurons and then by their tonic release in the hippocampus and cortex, would seem a viable strategy for the development of new therapeutics, including HMTM [6,22].”
BackgroundPin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation
Jeong, J., Usman, M., Li, Y., Zhou, X. Z., & Lu, K. P. (2024) · Cells · doi:10.3390/cells13090731 · Cited by 14
“Monoclonal antibodies against many intracellular proteins, including oncoproteins [251,252], tau [253–259], TDP43 [260], and RANs [261], to name a few, are used as therapeutics without engineering, with some being evaluated in human trials [262].”
BackgroundDendrimers—Novel Therapeutic Approaches for Alzheimer’s Disease
Mroziak, M., Kozłowski, G., Kołodziejczyk, W., Pszczołowska, M., Walczak, K., Beszłej, J. A., & Leszek, J. (2024) · Biomedicines · doi:10.3390/biomedicines12081899 · Cited by 12
“Oligomeric tau is the most toxic among all types; it allows the spreading of the disease by inducing tau seeding in healthy cells [17].”
BackgroundLive-cell visualization of tau aggregation in human neurons
Hurtle, B. T., Donnelly, C. J., Zhang, X., & Thathiah, A. (2024) · Communications Biology · doi:10.1038/s42003-024-06840-z · Cited by 12
“Furthermore, although several tau-targeted therapies have successfully prevented tau aggregation and propagation and promoted pathological tau clearance in pre-clinical models 15 , most tau-targeted AD clinical trials have failed due to insuf fi cient ef fi cacy 16 – 18 .”
Yan, Z.-J., Ye, M., Li, J., Zhang, D., & Yao, Y. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00853-w · Cited by 16
“Despite extensive research, effective parenchyma-based therapeutic strategies for AD have yet to be developed, largely due to the complexity and prolonged duration of the disease [3–8].”
Yan, W., Wu, J., Song, B., et al. (2019) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-019-01639-w · Cited by 12
RetractedDiscovery of Novel Drug Candidates for Alzheimer’s Disease by Molecular Network Modeling
Zhou, J., Li, Q., Wu, W., Zhang, X., Zuo, Z., Lu, Y., Zhao, H., & Wang, Z. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.850217 · Cited by 12
Manolopoulos, A., Andreadis, P., Malandris, K., Avgerinos, I., Karagiannis, T., Kapogiannis, D., Tsolaki, M., Τσάπας, Α., & Bekiari, E. (2019) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317519843720 · Cited by 13
“What is more, most of the potential anti-tau therapies have been discontinued mainly because of concerns about toxicity and lack of efficacy.(12)”
Background
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
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