All the Tau We Cannot See
Open accessAbstract
Alzheimer's disease (AD) was described in 1906 as a dementing disease marked by the presence of two types of fibrillar aggregates in the brain: neurofibrillary tangles and senile plaques. The process of aggregation and formation of the aggregates has been a major focus of investigation ever since the discoveries that the tau protein is the predominant protein in tangles and amyloid β is the predominant protein in plaques. The idea that smaller, oligomeric species of amyloid may also be bioactive has now been clearly established. This review examines the possibility that soluble, nonfibrillar, bioactive forms of tau—the “tau we cannot see”—comprise a dominant driver of neurodegeneration in AD.
AI snapshot
Written from the paper’s full text.
TL;DR
This review argues that soluble, nonfibrillar, bioactive forms of tau—the “tau we cannot see”—may be a dominant driver of neurodegeneration in Alzheimer’s disease, while fibrillar tangles correlate with but do not necessarily directly cause neuronal loss. It synthesizes neuropathological, mouse-model, biochemical, and plasma-biomarker evidence to support this hypothesis.
Key findings
- In autopsy stereology, more than 10-fold more neurons are lost than can be accounted for by tangles; resilient AD cases have the same number of neurofibrillary tangles as typical AD but minimal neuronal and synaptic loss.
- In Tg4510 P301L mice, doxycycline suppression leaves tangles unchanged for at least 6 weeks, yet neuronal loss essentially ceases and cognitive performance improves remarkably, implicating soluble tau rather than fibrils.
- Soluble oligomeric tau can be isolated from human AD brain; control samples lacked oligomeric tau, early eluting fractions had proteopathic seed-like ability, and cases with the most propagation potential had the fastest clinical course, replicated in two other clinical populations.
- Plasma phospho-tau assays distinguish biomarker-positive AD with comparable areas under the curve approaching 90% versus CSF; however, chronic renal disease influenced plasma tau181/217 as much as CNS abnormalities, and plasma NfL outperformed plasma phospho-tau181 for progression in a longitudinal study.
Methods
- Narrative review; no new primary data. It synthesizes cited human neuropathology, cryo-electron microscopy, mouse model, biochemical, and plasma biomarker studies.
- Main analysis is an interpretive synthesis around the hypothesis that soluble, nonfibrillar tau is bioactive and contributes to neurodegeneration, including discussion of specific studies and reported quantitative findings.
Limitations
- The paper states caution in extrapolating AD-versus-control distinctions from specialty clinics to the general population; Mielke et al. found comorbidities such as chronic renal disease influenced plasma tau181/217 as much as CNS abnormalities.
- The paper states it is not clear which tau assay/platform is most informative, nor whether assays predict stage rather than state; no link to clinical symptoms is well enough established to justify plasma tau as a primary trial endpoint.
- Evident from the text: this is a narrative review without systematic search or meta-analysis, and many cited studies are by Hyman and colleagues, so the synthesis may reflect the author’s group perspective.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 70 cited sources checked · 0 supported · 0 flagged
- Interpretationreasoning
Human neurons can be occupied by fibrils without neurotoxic consequence.
“This disconnection clearly points to the possibility that human neurons can be occupied by fibrils without neurotoxic consequence.”
Quote in the paperSubstantial claim - Premisecitation
Soluble tau, rather than fibrillar tau, impacts responsiveness of neurons to environmental stimuli in hippocampus after memory formation.
“From assessments of immediate early gene expression in the hippocampus after memory formation, it again appears that soluble tau, rather than fibrillar tau, seems to impact the responsiveness of neurons to environmental stimuli.”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationreasoning
Suppressing soluble forms of tau is key to improving neuronal health and integrity of neural circuits in the Tg4510 model.
“Instead, suppressing the soluble forms of tau being made by the transgene seems key to improving the neuronal health and integrity of neural circuits in this model.”
Quote in the paperSubstantial claim- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
- Premisecitation
More than 10-fold more neurons are lost in AD than can be accounted for by the number of tangles.
“Using stereological methods in patient autopsy material, Hyman and colleagues found that more than 10-fold more neurons are lost than can be accounted for by the number of tangles (16).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
Not checked in the free run.
- Premisecitation
In AD, there is a major discrepancy between the number of tangles and the amount of neuronal loss.
“While in general the pattern of anatomical locations that are affected by tangles is similar to the pattern of areas that undergo neuronal loss, there is a major discrepancy between the number of tangles and the amount of neuronal loss.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
Not checked in the free run.
- Premisecitation
In Tg4510 P301L mice, caspase activation and neuronal death often precede tangle formation.
“For example, through direct visualization of the cortex of Tg4510 P301L mice by multiphoton microscopy, Hyman and colleagues were able to determine that caspase activation, and neuronal death, appeared in many instances to precede tangle formation.”
Quote in the paperSubstantial claim0 of 2 sources checked- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
- Premisecitation
Soluble, oligomeric tau can be isolated from human AD brain using homogenization, centrifugation, and size exclusion chromatography.
“Soluble, oligomeric tau can also be isolated from human AD brain using simple homogenization, centrifugation, and size exclusion chromatography steps (67) (Figure 3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] source
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- Premisecitation
Calcium imaging reveals suppressed network activity in presence of tau overexpression independent of fibril formation.
“In another example of this same principle, calcium imaging using multiphoton microscopy reveals suppressed network activity in the presence of tau overexpression (in this case either wild-type tau or P301L tau), independent of fibril formation (23, 24).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Tau phosphorylation at specific sites overlapping AD sites diminishes tau's affinity for microtubules.
“It is well established that tau phosphorylation, especially at specific sites that overlap with the sites that are phosphorylated in AD, diminishes the affinity of tau for microtubules (4, 26–29).”
Quote in the paperSubstantial claim0 of 5 sources checked - Premisecitation
Tangles forming did not lead to neuronal death over several-month imaging period in Tg4510 P301L mice.
“Indeed, tangles forming did not lead to neuronal death over the course of the several-month imaging period (43, 51).”
Quote in the paperSubstantial claim0 of 2 sources checked- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
- Interpretationreasoning
Tau mislocalization from axon to cytoplasm and dendrites can be viewed as a primary lesion with loss of function and gain of function.
“This mislocalization can be viewed as a primary lesion, with subsequent loss of function (it no longer stabilizes axonal microtubules) and gain of function (it interacts with cytoplasmic constituents that it normally would not interact with).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Tau stabilizes microtubules.
- Interpretationreasoning
Soluble species of tau are important in the pathophysiology of AD.
“These results also reinforce the idea that soluble species of tau are important in the pathophysiology of AD.”
Quote in the paperSubstantial claim - Premisecitation
Resolution of soluble forms of tau is sufficient to normalize morphology of dystrophic neurites around plaques.
“Another example of tau-related lesions, the dystrophic neurites around plaques, also implicates the role of soluble rather than fibrillar species since the resolution of soluble forms of tau is sufficient to lead to normalization of the morphology (25, 53).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Plasma tau measurement could be used as a screening test in early-stage clinical trials to enrich trial participation with individuals more likely to have AD pathology.
“Plasma tau measurement could thus be used as a screening test in early-stage clinical trials to enrich trial participation with individuals more likely to have AD pathology (76, 77, 90).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Within the AD cohort, some samples contained more bioactive, propagation-prone material per unit tau than others.
“Moreover, within the AD cohort, some samples seemed to contain more bioactive, propagation-prone material (per unit of tau protein) than others.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] source
Not checked in the free run.
- Premisecitation
The observation that characteristics of soluble tau correlate with aggressiveness of clinical phenotype has been replicated in two other clinical populations.
“This observation—that the characteristics of soluble tau correlate with how aggressive the clinical phenotype is—has already been replicated in two other clinical populations (68, 69).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
LRP1 appears to be a primary mechanism subverting uptake of soluble extracellular tau, allowing it to escape degradation and be released to cytoplasm.
“For example, the multifunctional receptor LRP1 appears to be a primary mechanism subverting uptake of soluble extracellular tau (58, 59), so that it can at least partly escape degradation and be released to the cytoplasm.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Fibril formation is not necessary for mitochondrial abnormalities, synaptic loss/dysfunction, altered axonal transport, and activation of cell death pathways ascribed to tau mislocalization or oligomerization.
“While distinguishing cause and effect is complex, the data support the notion that fibril formation, per se, is not necessary for these effects.”
Quote in the paperSubstantial claim - Premisecitation
In vitro studies using soluble phospho-tau oligomers find substantial alterations in nuclear-cytoplasmic transport.
“Not only is there clear morphological evidence of nuclear alterations in AD, but also, in vitro studies using soluble phospho-tau oligomers as a perturbant find substantial alterations in nuclear–cytoplasmic transport (e.g., 31, 33, 37, 54).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation
Reduction of tau mRNA using zinc finger gene therapy in mice with wild-type endogenous tau improves behavior and morphological indices of neuronal damage in context of Aβ deposits.
“Finally, reduction of tau mRNA using zinc finger gene therapy approaches (in mice with wild-type endogenous levels of tau) leads to improvements in behavior and morphological indices of neuronal damage in the context of Aβ deposits (25), consistent with the idea that soluble rather than insoluble species lead to the neuronal phenotype.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] source
Not checked in the free run.
- Premisecitation
Mielke et al. showed that comorbidities such as chronic renal disease influenced plasma tau 181 and 217 levels as much as CNS abnormalities.
“Mielke et al. recently showed that, although plasma tau 181 and 217 were elevated in AD samples, comorbidities such as chronic renal disease influenced levels as much as the presence of CNS abnormalities (86).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [86] source
Not checked in the free run.
- Premisenone given
In Alzheimer's disease, tau protein accumulates in multiple forms.
“In AD, tau protein accumulates in multiple forms.”
Quote in the paperSubstantial claim - Interpretationreasoning
The clinical significance of plasma tau moving towards normal in Aduhelm trial is uncertain because link to clinical symptoms is not well enough established to justify plasma tau as primary endpoint.
“The clinical significance of this outcome is uncertain, since a link to clinical symptoms is not yet well enough established to justify plasma tau as a primary endpoint for a trial.”
Quote in the paperSubstantial claim - Premisenone given
Soluble oligomeric species can be released from neurons.
“can be released from neurons”
Quote in the paperSubstantial claim - Interpretationreasoning
Misfolded soluble oligomeric species may be bioactive.
“These emerging data suggest that in addition to fibrillar lesions, the misfolded soluble oligomeric species—which are undetectable by classical stains that detect fibrils—may be bioactive and contribute to neurodegeneration.”
Quote in the paperSubstantial claim - Premisenone given
Soluble oligomeric species occur in the cytoplasm.
“soluble, oligomeric species that occur in the cytoplasm”
Quote in the paperSubstantial claim - Interpretationreasoning
Misfolded soluble oligomeric species may contribute to neurodegeneration.
“These emerging data suggest that in addition to fibrillar lesions, the misfolded soluble oligomeric species—which are undetectable by classical stains that detect fibrils—may be bioactive and contribute to neurodegeneration.”
Quote in the paperSubstantial claim - Premisenone given
These classical fibrils appear to be essentially identical from patient to patient.
“These fibrils appear to be essentially identical from patient to patient.”
Quote in the paperSubstantial claim - Premisenone given
Soluble oligomeric species can induce a wide variety of potentially toxic phenotypes.
“can induce a wide variety of potentially toxic phenotypes”
Quote in the paperSubstantial claim - Premisenone given
In contrast to fibrils, these oligomers (and their bioactivity as measured by propagation) vary to some extent among individual patients.
“In contrast to the fibrils, these oligomers (and their bioactivity as measured by propagation) vary to some extent among individual patients”
Quote in the paperSubstantial claim - Premisenone given
This heterogeneity in oligomers correlates with rate of progression of the disease process across neural systems.
“this heterogeneity correlates with rate of progression of the disease process across neural systems”
Quote in the paperSubstantial claim - Premisenone given
Soluble oligomeric species can be taken up by recipient cells.
“taken up by recipient cells”
Quote in the paperSubstantial claim - Premisecitation
In the Aduhelm trial, a small subset of individuals had plasma tau levels move 'towards normal.'
“The best published data are from the Aduhelm trial (93), where a small subset of individuals was analyzed and their plasma tau levels moved “towards normal.””
Quote in the paperSubstantial claim0 of 1 sources checked- cites [93] Budd Haeberlein S, 2022, J. Prev. Alzheimers Dis.
Not checked in the free run.
- May combine two claims. 15
- Classified as probably not a substantial claim. 2
May combine two claims.
FindingcitationCases with most marked propagation potential had the fastest clinical course and characteristic patterns of post-translational modifications.
“In examining the clinical records, we found that those cases with the most marked propagation potential also had the fastest clinical course and had characteristic patterns of post-translational modifications (10, 11).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningTangles (and Pick bodies) correlate with neuronal loss but are not critical mediators of neuronal loss.
“the most straightforward interpretation of these data is that tangles (and Pick bodies) correlate with neuronal loss but are not critical mediators of neuronal loss.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe presence of tau fibrils per se does not lead to ongoing neuronal death or cognitive deficit in the Tg4510 model.
“Thus, the presence of the tau fibrils, per se, does not lead to ongoing neuronal death or cognitive deficit.”
Quote in the paperSubstantial claim- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
May combine two claims.
PremisecitationIn resilient AD cases, the number of neurofibrillary tangles is the same as in typical AD patients, although neuronal and synaptic loss is minimal.
“Moreover, in rare instances of AD in which cognition is relatively preserved (resilient cases), the number of neurofibrillary tangles is the same as in typical AD patients, although the amount of neuronal and synaptic loss is minimal (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] source
Not checked in the free run.
May combine two claims.
Interpretationnone givenSoluble, nonfibrillar tau plays a major role in toxicity and in propagation of tau lesions across neural systems in AD.
“By contrast with this long-held view that fibril formation is the key toxic event in AD, mounting evidence suggests that soluble, nonfibrillar tau also plays a major role both in toxicity and in propagation of tau lesions across neural systems.”
Quote in the paperSubstantial claim- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
May combine two claims.
PremisecitationIn Tg4510 mice, suppression of the P301L tau transgene leads to unchanged tangle number, cessation of neuronal loss, and improved cognitive performance.
“Intriguingly, suppression of the transgene at that point leads to a striking change in phenotype: The tangles remain unchanged in number (for at least 6 weeks), neuronal loss essentially ceases, and the cognitive performance of the animals improves remarkably.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] source
Not checked in the free run.
- Rests on an assumption: Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
May combine two claims.
PremisecitationPlasma tau has emerged as a marker of neuronal distress and appears in several neurodegenerative diseases, including preclinical AD.
“Like NfL (neurofilament light chain), plasma tau has emerged as a marker of neuronal distress. It appears in several different neurodegenerative diseases, including importantly even preclinical AD patients (76–85).”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [76] source
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- cites [77] source
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- cites [84] source
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- cites [85] source
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May combine two claims.
PremisecitationA recent large study comparing plasma to CSF tau showed comparable areas under the curve (approaching 90%) for each phospho-tau assay, with plasma values largely paralleling CSF values in distinguishing biomarker-positive AD.
“In fact, a recent large study comparing plasma to cerebrospinal fluid tau showed that there were comparable areas under the curve (approaching 90%) for each of the phospho-tau assays measured; plasma values largely paralleled cerebrospinal fluid values (87) in distinguishing individuals with biomarker-positive AD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [87] source
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May combine two claims.
PremisecitationTau-induced suppression of neural networks can be relieved by turning off transgene expression, with restoration time consistent with soluble tau half-life, not fibrillar tau.
“Tau-induced suppression of neural networks can be relieved by turning off expression of the transgene, leading to rapid restoration of function in a time frame consistent with the half-life of soluble tau protein, not fibrillar tau.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationControl samples did not contain oligomeric tau species, and early eluting fractions from AD brain contained tau with proteopathic seed-like ability.
“In carrying out these experiments, Hyman and colleagues noticed that control samples did not contain any oligomeric tau species and that the early eluting fractions contained tau that had proteopathic seed-like ability (67).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] source
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May combine two claims.
PremisecitationMitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways have been implicated as consequences of tau mislocalization or oligomerization.
“Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways (including caspase activation and inflammatory responses) have all been directly or indirectly implicated as consequences of tau mislocalization or oligomerization (20, 40, 43–52).”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [20] source
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Interpretationown dataOligomeric forms of tau are proteopathic seed-competent species that may contribute to neurodegenerative phenotypes.
“Our data suggest that the oligomeric forms are proteopathic seed-competent species that may well contribute to neurodegenerative phenotypes.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPlasma tau likely gives information about whether the brain contains neurofibrillary tangles, and plasma tau elevation seems to precede overt clinical symptoms.
“Plasma tau likely does give information about whether the brain contains neurofibrillary tangles, and, like early Braak stages, plasma tau elevation seems to precede overt clinical symptoms (77, 89).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationPlasma tau appears to be more specific for AD pathology compared to frontotemporal dementia and chronic traumatic encephalopathy, but is increased in prion disease.
“It appears to be more specific for AD pathology, at least compared to frontotemporal dementia and chronic traumatic encephalopathy (85, 91, 92), but it is increased in prion disease (83).”
Quote in the paperSubstantial claim0 of 4 sources checkedProbably not a substantial claim: may not pass S4 (based).
Premisenone givenMisfolded soluble oligomeric species are undetectable by classical stains that detect fibrils.
“which are undetectable by classical stains that detect fibrils”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe classical fibrils that were initially identified and named neurofibrillary tangles by Alzheimer over a century ago have recently been further characterized on a structural level by cryo-electron microscopy.
“The classical fibrils that were initially identified and named neurofibrillary tangles by Alzheimer over a century ago have recently been further characterized on a structural level by elegant cryo–electron microscopy work.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationMost studies do not show that levels of plasma phospho-tau predict rate of progression, and plasma NfL outperformed plasma phospho-tau 181 in a longitudinal study.
“Most studies do not show that the levels of plasma phospho-tau predict the rate of progression, and in a longitudinal study, plasma NfL outperformed plasma phospho-tau 181 in this regard (84).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [84] source
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The authors state this as an assumption.
Tau stabilizes microtubules.
“Tau is thus assumed to stabilize microtubules, and it likely has a role in axonal transport.”
The paper relies on this without support.
Animal models of tauopathy (e.g., Tg4510) recapitulate key aspects of human AD neurodegeneration.
“One of the most commonly used models is the Tg4510 strain, developed by Dr. Karen Ashe, in which the animals develop progressive tau inclusions, neuronal loss, and cognitive impairments consequent to expression of the P301L tau transgene (18).”
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?
Soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau, including NFTs.
“These findings indicate that soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau (including NFT), the “tau we can see”.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [25]
The citation lists haven’t been fetched yet
References 91 · Cited by 39
Research works printed but not linked: 3
- Tai HC, 2014, Acta Neuropathol. Commun., 2, 146
- Cullen NC, 2022, Alzheimers Dement., 2022, 1
- Budd Haeberlein S, 2022, J. Prev. Alzheimers Dis., 9, 197
- Authors
- Hyman, B.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Hyman, Bradley
- ORCID
- Hyman, Bradley
- Venue
- Annual Review of Medicine
- Publisher
- Annual Reviews
- Published
- 2023-01-27
- Volume
- 74
- Issue
- 1
- Pages
- 503-514
- ISSN
- 0066-4219 (ISSN-L)
- 1545-326X
- PMC
- PMC11783578
- OpenAlex
- W4309087248
- Semantic Scholar
- 7c44801a59fdde4bfb2efe4fe06684359fd0d79e
- Cited by
- 39
- References
- 91
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 10 · 2023: 10
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Annual Review of Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Funders
- National Institute on Aging (RF1AG073236, RF1AG058674, R56AG061196, RF1AG059789, R01AG073236, P30AG062421)
- 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, neurofibrillary tangles, amyloid plaques, amyloid-beta, oligomeric amyloid, soluble tau, neurodegeneration, protein aggregation, fibrillar aggregates
- MeSH terms
- Alzheimer Disease, Brain, Humans, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins
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