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Cited by 1,113Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau-targeting therapies for Alzheimer disease

Open access
Congdon, Erin E., Sigurdsson, Einar M.·2018·Nature Reviews Neurology
DOI 10.1038/s41582-018-0013-zPMC PMC6463489
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

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

Integrity signals

Registry

Crossref · 10.1038/s41582-018-0013-z

Cites

231 of 231 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Findingcitation

    Aβ immunotherapy has noteworthy but modest effects on tau pathology.

    “Some data indicate that Aβ immunotherapy has noteworthy but modest effects on tau pathology.”
    Quote in the paperSubstantial claim
  • Findingcitation

    In phase II trials, the anti-Aβ antibody bapineuzumab reduced CSF phospho-tau levels in patients with AD.

    “in phase II trials, the anti-Aβ antibody bapineuzumab reduced CSF phospho-tau levels in patients with AD182,183”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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  • Findingcitation

    Antibody fragments have been shown to reduce tau levels in vivo.

    “Moreover, antibody fragments have been shown to reduce tau levels in vivo225,226.”
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    • cites [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

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    • cites [226] Ising, C. et al. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J. Exp. Med. 214, 1227–1238 (2017). source

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  • Findingcitation

    In the first active immunization trial, the AN-1792 vaccine seemed to show some ability to clear Aβ plaque-associated tau lesions through plaque removal.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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

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    • cites [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

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    • cites [181] Boche, D. et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Aβ42 immunisation in Alzheimer’s disease. Acta Neuropathol. 120, 13–20 (2010). source

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  • Findingcitation

    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 epitope, came from our group.

    “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.”
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    • cites [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

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    • cites [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

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    • cites [187] Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).

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    • cites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).

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    Findingcitation

    Immunization with these agents reduced pathological tau levels and attenuated the behavioural phenotypes associated with the tauopathy, demonstrating the feasibility of these related interventions.

    “Immunization with these agents reduced pathological tau levels and attenuated the behavioural phenotypes associated with the tauopathy, demonstrating the feasibility of these related interventions.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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

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    • cites [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

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    • cites [187] Asuni, A. A., Quartermain, D. & Sigurdsson, E. M. Tau-based immunotherapy for dementia [abstract]. Alzheimers Dement. 2 (Suppl.), O2-05-04 (2006).

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    • cites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).

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

    Findingcitation

    The pSer396/404 region was the first to be studied and has since been targeted by several groups.

    “As mentioned above, the pSer396/404 region was the first to be studied and has since been targeted by several groups186, 188,201–208.”
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    • cites [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 in the free run.

    • cites [188] Boutajangout, A., Ingadottir, J., Davies, P. & Sigurdsson, E. M. Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy [abstract]. Alzheimers Dement. 6 (Suppl.), P3–427 (2010).

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    • cites [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

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    • cites [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

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    • cites [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

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    • cites [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

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    • cites [205] Ittner, A. et al. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice. J. Neurochem. 132, 135–145 (2015). source

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    • cites [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

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    • cites [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

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    • cites [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

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    Findingreasoning

    Reductions in pathological tau are achieved with few reported adverse effects.

    “Reductions in pathological tau are achieved with few reported adverse effects, and the long-lasting immune response makes active immunization a promising option.”
    Quote in the paperSubstantial claim

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    Findingcitation

    In mice, tau vaccination has been reported to cause toxicity when administered in conjunction with strong T-helper 1-inducing adjuvants, which are not approved for use in humans.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [200] Rozenstein-Tsalkovich, L. et al. Repeated immunization of mice with phosphorylated-tau peptides causes neuroinflammation. Exp. Neurol. 248, 451–456 (2013). source

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    Findingcitation

    Monoclonal antibodies against the amino-terminal or repeat domain (306-320) region, oligomeric tau, misfolded tau, pSer202, pThr231, pSer409, pSer413 and pSer422 have proved to be efficacious in tauopathy models.

    “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.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    • cites [212] Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M. & Diamond, M. I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012). source

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    • cites [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

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    • cites [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

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    • cites [215] Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015). source

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    • cites [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

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    • cites [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

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    • cites [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

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    Findingcitation

    There was no evidence of an astrocyte response or significant differences in body weight in the vaccinated mice compared with vehicle-treated animals.

    “There was no evidence of an astrocyte response or significant differences in body weight in the vaccinated mice compared with vehicle-treated animals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Findingcitation

    In Tau.P301L mice, serum samples from mice 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Findingcitation

    Fc receptors are expressed on neurons and seem to be the main route of entry for anti-tau antibodies.

    “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.”
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    • cites [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).

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    • cites [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

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    • cites [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

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    • cites [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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    Findingcitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Findingcitation

    Anti-tau antibodies can cross into the brain and enter neurons, where they primarily colocalize with endosomal and lysosomal markers.

    “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.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [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 in the free run.

    • cites [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

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    • cites [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

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    • cites [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 in the free run.

    • cites [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

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    • cites [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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    • cites [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

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    • cites [230] Krishnaswamy, S. et al. Antibody-derived in vivo imaging of tau pathology. J. Neurosci. 34, 16835–16850 (2014). source

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    Findingcitation

    Tau-expressing cells secrete normal and pathological tau, which can be taken up by other cells and induce seeding of tau pathology.

    “Tau-expressing cells secrete normal and pathological tau234, which can be taken up by other cells and induce seeding of tau pathology54,64,228.”
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    • cites [234] Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).

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    • cites [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

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    • cites [64] Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017). source

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    • cites [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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    Findingreasoning

    The entry of these antibodies into neurons is mainly receptor-mediated but can also occur via bulk endocytosis to some extent.

    “The entry of these antibodies into neurons is mainly receptor-mediated but can also occur via bulk endocytosis to some extent.”
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    Findingcitation

    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.

    “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.”
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    • cites [241] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01850238 (2015).

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    • cites [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

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    Findingcitation

    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 only.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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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    Findingown data

    Adverse effects of this vaccine in rats were limited to inflammation at the injection site, and the treatment did not produce any deleterious immunological responses.

    “Adverse effects were limited to inflammation at the injection site, and the treatment did not produce any deleterious immunological responses.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Even healthy cells can release tau into the culture medium, where it can be endocytosed.

    “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.”
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    • cites [234] Medina, M. & Avila, J. The role of extracellular tau in the spreading of neurofibrillary pathology. Front. Cell. Neurosci. 8, 113 (2014).

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    • cites [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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    Findingcitation

    In phase I testing, almost all of the participants (29 of 30) developed an immunoglobulin G response, and no instances of encephalitis or oedema were reported.

    “Almost all of the participants (29 of 30) developed an immunoglobulin G response, and no instances of encephalitis or oedema were reported.”
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    • cites [241] US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01850238 (2015).

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    • cites [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

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    Findingcitation

    In transgenic mice, RG7345 was shown to enter neurons and reduce tau pathology.

    “In transgenic mice, RG7345 was shown to enter neurons and reduce tau pathology224.”
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    • cites [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

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    Findingcitation

    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 CSF.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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).

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    No adverse immune reactions were seen; in fact, microglial activation was reduced in the treated animals.

    “No adverse immune reactions were seen; in fact, microglial activation was reduced in the treated animals213,239.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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

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    • cites [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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  • May combine two claims.

    Findingcitation

    Preclinical testing showed that UCB0107 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 tau.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Multiple groups have tau antibodies in development, but not yet in clinical trials.

    “In addition, multiple groups have tau antibodies in development, but not yet in clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Bright, J. et al. Human secreted tau increases amyloid-beta production. Neurobiol. Aging 36, 693–709 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    Curcumin is limited by its bioavailability, and has yet to demonstrate efficacy in humans with tauopathy.

    “Furthermore, curcumin is limited by its bioavailability, and has yet to demonstrate efficacy in humans with tauopathy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    CSF tau levels are increased in AD but not in the other tauopathies.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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

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    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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 cognition.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    In AD and PART, 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 disease.

    “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.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Active GSK3β and its regulator JNK are associated with neurofibrillary pathology and are upregulated in AD.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Tell, V. & Hilgeroth, A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci. 7, 189 (2013). source

      Not checked in the free run.

    • cites [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).

      Not checked in the free run.

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

    Premisecitation

    Hippocampal-sparing and limbic-predominant subtypes are thought to constitute approximately 25% of AD cases.

    “However, hippocampal-sparing and limbic-predominant subtypes are thought to constitute ~25% of AD cases13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 upregulated.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Sontag, J. M. & Sontag, E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front. Mol. Neurosci. 7, 16 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    N-glycosylation of tau is increased in AD and is thought to promote phosphorylation and pathological conformational changes.

    “Conversely, N-glycosylation of tau, which is thought to promote phosphorylation and pathological conformational changes, is increased in AD9,35.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [35] Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cell models, soluble oligomeric tau can induce seeding of native tau, and small tau aggregates isolated from patients or animals with AD can induce tau pathology in mice.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [64] Goedert, M. & Spillantini, M. G. Propagation of Tau aggregates. Mol. Brain 10, 18 (2017). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In MCI and AD, the pattern of kinase activation in the mTOR pathway is altered and expression of other key autophagy-related proteins is reduced in the brain.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetylation contributes to tau pathology by inducing tau cleavage, preventing ubiquitin binding and impeding tau turnover.

    “Acetylation also contributes to tau pathology by inducing tau cleavage, preventing ubiquitin binding and impeding tau turnover8,35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010). source

      Not checked in the free run.

    • cites [35] Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Truncation inhibits the ability of tau to bind to microtubules and promotes tau aggregation, mitochondrial dysfunction and synaptic deficits.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [39] Jadhav, S. et al. Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front. Cell. Neurosci. 9, 24 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AD, brain neurons show a reduction in the number and length of microtubules, reduced levels of acetylated tubulin, and axonal swellings containing vesicles and organelles.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [43] Zhang, F. et al. Posttranslational modifications of α-tubulin in Alzheimer disease. Transl Neurodegener. 4, 9 (2015). source

      Not checked in the free run.

    • cites [44] Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307, 1282–1288 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CSF tau levels are higher in AD than in controls, but the levels decrease as the disease progresses despite the accrual of NFTs.

    “Although CSF tau levels are higher in AD than in controls, the levels decrease as the disease progresses, despite the accrual of NFTs56.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Fagan, A. M. et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci. Transl Med. 6, 226ra30 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neurons containing tangles have fewer synapses and reduced levels of synaptophysin mRNA compared with tangle-free neurons.

    “Neurons containing tangles also have fewer synapses and reduced levels of synaptophysin mRNA compared with tangle-free neurons52,53.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oligomeric tau is the probable candidate for the most toxic species in tauopathies and is present in the brain at early stages of MCI and AD.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau oligomers promote toxicity in cell models to a greater extent than filamentous tau, and are linked to neurodegeneration and cognitive phenotypes in vivo.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    MK-8719 was well tolerated in healthy individuals, and O-GlcNAcylated protein levels in peripheral blood mononuclear cells increased in a dose-dependent manner.

    “The drug was well tolerated and the findings support further development134.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a recent study, patients with AD given very low doses of lithium (300 μg daily) for 15 months showed stabilization of cognitive symptoms, whereas placebo-treated patients showed cognitive decline.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models of AD, tideglusib reduces tau phosphorylation, Aβ plaque burden, memory deficits, cell death and astrocytosis.

    “In animal models of AD, tideglusib reduces tau phosphorylation, Aβ plaque burden, memory deficits, cell death and astrocytosis118,119.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    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 imaging.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of autophagosome processing in neurons can lead to increased production of Aβ, which can in turn further inhibit protein digestion.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    Rolipram improves cognition and reduces pathology in Aβ and tauopathy mice, and in rats treated with exogenous Aβ.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical testing, epothilone D increased microtubule numbers and reduced the number of axons with abnormal morphology in young and aged tau transgenic mice.

    “In preclinical testing, epithilone D increased microtubule numbers and reduced the number of axons with abnormal morphology in young157 and aged158 tau transgenic mice.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

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  • May combine two claims.

    Premisecitation

    In other mouse models of tauopathy, epothilone D improved cognition and reduced tau pathology and tau-related changes in microtubule dynamics.

    “In other mouse models of tauopathy, the drug improved cognition, and reduced tau pathology and tau-related changes in microtubule dynamics159.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    Tau is directly toxic to cells and is also a mediator of Aβ toxicity.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with MCI, lithium treatment significantly reduced phospho-tau levels in CSF and improved cognitive performance.

    “In patients with MCI, lithium treatment significantly reduced phospho-tau levels in CSF and improved cognitive performance127,128.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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 AD, but when the entire study cohort was analysed, tideglusib produced no significant improvements.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Lovestone, S. et al. A phase II trial of tideglusib in Alzheimer’s disease. J. Alzheimers Dis. 45, 75–88 (2015). source

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  • May combine two claims.

    Premisecitation

    In mouse models, tau knockout has few adverse effects, presumably because other microtubule-associated proteins can compensate for loss of the tau protein.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Ke, Y. D. et al. Lessons from tau-deficient mice. Int. J. Alzheimers Dis. 2012, 873270 (2012).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methylene blue was effective at reducing tau pathology and improving cognitive phenotypes in transgenic mouse models of tauopathy.

    “This agent was effective at reducing tau pathology and improving cognitive phenotypes in transgenic mouse models of tauopathy137.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    In preclinical testing, salsalate reduced p300 HAT activity, leading to reduced tau pathology, preserved hippocampal volume and improved cognition in transgenic mice.

    “In preclinical testing, salsalate reduced p300 HAT activity, leading to reduced tau pathology, preserved hippocampal volume and improved cognition in transgenic mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Min, S. W. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 21, 1154–1162 (2015). source

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    Premisecitation

    In patients with moderate to severe AD, memantine promoted small short-term improvements in cognition, and it also seemed to provide modest benefits in FTD.

    “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.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aβ immunotherapies have been largely unsuccessful, possibly because they were administered only after the symptoms of AD had become apparent.

    “To date, Aβ immunotherapies have been largely unsuccessful, possibly because they were only administered once the symptoms of AD had become apparent173–178.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [177] Wisniewski, T. & Drummond, E. Developing therapeutic vaccines against Alzheimer’s disease. Expert Rev. Vaccines 15, 401–415 (2016). source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

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

    Study design and conductnone given

    The ability of the antibody to enter neurons was not assessed.

    “The ability of the antibody to enter neurons was not assessed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In general, both active and passive immunization 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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Many of the compounds under investigation might exert effects through more than one pathway.

    “Adding to the complexity is the fact that many of the compounds under investigation might exert effects through more than one pathway.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    On numerous occasions, preclinical success in animal models has failed to translate into benefits in humans.

    “On numerous occasions, preclinical success in animal models has failed to translate into benefits in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    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).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Anti-tau antibodies that primarily work extracellularly should probably target amino acids 150-250, and might only work in AD.

    “Therefore, anti-tau antibodies that primarily work extracellularly should probably target amino acids 150–250, and might only work in AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pathogenesis of tauopathies is likely to differ.

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

    Study design and conductreasoning

    As an early-stage trial, the number of participants is insufficient for efficacy assessment.

    “As an early-stage trial, the number of participants is insufficient for efficacy assessment.”
    Quote in the paperNot a substantial claim
63 of 63

  • 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.”
5 of 5

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?

  • Most tau targeted therapies undergoing clinical trials are immune-based therapies due to toxicity or lack of efficacy of other anti-tau therapies.

    “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]

    The Tau immunotherapies section says many tau vaccines and antibodies had moved into clinical development, and the Conclusions describe multiple immunization trials. The Conclusions also note disappointing clinical results for some other approaches. Neither passage establishes that most ongoing tau-targeted trials were immune-based or that toxicity or lack of efficacy of other anti-tau therapies caused that distribution; page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Multiple clinical trials based on tau active and passive immunization are ongoing.

    “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]

  • Passive transfer of anti-tau antibodies is an effective method, since tau can be secreted into the extracellular space and some antibodies can enter neurons.

    “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 animal models, antibodies that bind selectively to phosphorylated tau have shown promise in lowering tau pathology.

    “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]

  • Many tau-targeting methods have had difficulties in the clinic, frequently due to toxicity or ineffectiveness.

    “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]

Cites

Flagged first, then by citations

4 of the 235 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Fagan, T. In first phase 3 trial, the tau drug LMTM did not work. Period. Alzforum http://www.alzforum.org/news/conference-coverage/first-phase-3-trial-tau-drug-lmtm-did-not-work-period#show-more (2016).
  2. Fagan, T. Tau inhibitor fails again — subgroup analysis irks clinicians at CTAD. Alzforum http://www.alzforum.org/news/conference-coverage/tau-inhibitor-fails-again-subgroup-analysis-irks-clinicians-ctad (2016).
  3. [No authors listed.] Biogen licenses phase 2 anti-tau antibody from Bristol-Myers Squibb. Biogen http://media.biogen.com/press-release/corporate/biogen-licenses-phase-2-anti-tau-antibody-bristol-myers-squibb (2017).
  4. West, T. et al. Safety, tolerability and pharmacokinetics of ABBV-8E12, a humanized anti-tau monoclonal antibody, in a Phase I, single ascending dose, placebo-controlled study in subjects with progressive supranuclear palsy. J. Prev. Alzheimers Dis. 3, 285 (2016).
  5. 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).
  6. 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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Related

Authors
Congdon, E. E., & Sigurdsson, E. M.
Affiliations
New York University (US)
Corresponding author
Sigurdsson, Einar M.
ORCID
Venue
Nature Reviews Neurology
Publisher
Springer Science and Business Media LLC
Published
2018-06-12
Volume
14
Issue
7
Pages
399-415
ISSN
  • 1759-4758 (ISSN-L)
  • 1759-4766
DOI
10.1038/s41582-018-0013-z
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 · 2014: 1
FWCI
14.47
Type
journal article
Language
en
Open access
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
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, tau protein, tau immunotherapy, amyloid-beta, neurofibrillary tangles, tau aggregation, kinase inhibition, microtubule stabilization, clinical trial failure
MeSH terms
Alzheimer Disease, Animals, Humans, tau Proteins

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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