Pathogenesis and pathology of tauopathies …

Neurobehavioral & Cognitive Disorders

Updated 11.29.2023
Released 06.13.2022
Expires For CME 11.29.2026

Pathogenesis and pathology of tauopathies

Authors: Hannah Noah MD MPH, Andrew E Budson MD

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Editor: Howard S Kirshner MD

Pathogenesis and pathology of tauopathies

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Introduction

Overview

Diseases with pathologic tau protein inclusions in neurons or glia are known as tauopathies. Tau pathology causes several neurodegenerative diseases, including Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, Pick disease, and chronic traumatic encephalopathy. Misfolded tau is an attractive therapeutic target, and research has advanced our understanding of the pathophysiology of tauopathies. Although successful disease-modifying therapies directly targeting tau remain elusive, 2023 heralded the arrival of lecanemab, an anti-amyloid drug targeting the common and secondary tauopathy, Alzheimer disease.

Key points

	• Tau is a protein that stabilizes microtubules to facilitate axonal transport and maintain neuronal integrity.
	• Tauopathies are diverse neurodegenerative diseases characterized by inclusions of abnormal tau deposited in different areas or cells of the brain, leading to heterogeneous clinical features.
	• Pathologically, abnormal tau causes disease when insoluble filaments aggregate in neurons and astroglial cells and propagate between cells in neural networks in a prion-like fashion.
	• Although several drugs targeting tauopathies have failed in clinical trials, promising new therapies continue to emerge.

Historical note and terminology

In 1907, Alois Alzheimer published a short paper describing plaques and tangles in the brain of a patient with presenile dementia. This is the first known description of tau pathology (13; 16). Electron microscopy performed by Michael Kidd in 1963 then identified paired helical filament as the prominent structural component in neurofibrillary tangles (25). In 1975, Weingarten described a “heat stable protein essential for microtubule assembly” and named the protein “tau” (56). Tau was subsequently identified as the major structural component of the neurofibrillary tangles seen in Alzheimer disease in 1986 (17).

In the 1990s, researchers identified autosomal dominant mutations in the MAPT gene associated with a familial syndrome of frontotemporal dementia and parkinsonism. This group of disorders was labeled “frontotemporal dementia and parkinsonism linked to chromosome 17” (FTDP-17). In one of the families studied, the disorder was named “multiple system tauopathy with presenile dementia.” This resulted in the introduction of the term “tauopathy,” a term that now encompasses disorders characterized by pathologic tau protein deposition (12).

Given that the MAPT gene encodes tau, these disorders provided evidence that aberrant tau can cause neurodegenerative disorders (21; 40). Studies of pathologic changes in the brains of Alzheimer patients have further supported the role of pathologic tau in neurodegeneration (43). Furthermore, a study of patients with progressive supranuclear palsy found a correlation between pathologic tau burden and degree of cognitive impairment, particularly executive dysfunction (27). Overall, the presence of pathologic tau correlates well with the degree of clinical impairment.

Description

	• Tau functions as a microtubule stabilizer to facilitate axonal transport and maintain neuronal integrity.
	• Hyperphosphorylation of tau likely leads to insoluble filament formation and neurofibrillary tangles that aggregate in cells and exhibit toxic effects.
	• Animal studies have shown that abnormal aggregates of tau can propagate between cells in a prion-like fashion and ultimately cause diverse diseases based on the distribution of aggregates.

The function and expression of tau. Microtubules play a critical role in supporting the structural needs of a neuron as well as facilitating intracellular transport (23). The normal physiological function of tau is to support the assembly and stabilization of microtubules (49; 26). Binding of tau promotes microtubules in their polymerized state and thereby facilitates axonal transport and maintains neuronal integrity (32).

The MAPT gene encoding tau is on chromosome 17q21. In early human development, tau is present throughout the neuron. In developed neurons, however, tau is primarily located in the axons, where it normally contributes to the maintenance of axonal health (16; 49). Grey matter expresses MAPT at higher concentrations than white matter or cerebellum. Tau has also been found to have a physiologic role in dendrites and to be expressed in low levels in glial cells (28).

In the human brain, alternative splicing of the MAPT gene produces six isoforms. Alternative splicing of exons 2 and 3 results in tau protein with either 0, 1, or 2 amino-terminal inserts. The isoforms are labeled 0N, 1N, or 2N based on the number of amino-terminal inserts present. Additionally, alternative splicing of exon 10 creates tau with either three or four microtubule binding regions. These isoforms are respectively labelled 3R and 4R. The fetal brain produces only 0N3R tau, whereas the adult brain produces all six isoforms. Importantly, the healthy adult brain expresses 3R and 4R tau in a 1:1 ratio (16).

Pathologic tau. Tau undergoes a variety of post-translational modifications. The most relevant post-translational modification to the tauopathies is likely phosphorylation, which may play a role in the trafficking and localization of tau in the cell. Notably, phosphorylation reduces tau’s affinity for microtubules. The hyperphosphorylation of tau may allow tau to aggregate and form pathologic oligomers, which, in turn, promote the formation of insoluble paired helical filaments that form the neurofibrillary tangles in Alzheimer disease, suggesting that tau hyperphosphorylation plays a role in disease pathogenesis (07; 16). More research is needed to determine whether hyperphosphorylated tau is a cause or consequence of the tauopathies (41). Other post-translational modifications that may contribute to the development of pathologic tau include acetylation, truncation, ubiquitination, glycation, and SUMOylation (38; 41).

The correlation between pathologic tau burden and disease severity suggests that tau mediates cell death. The Braak rating scale for Alzheimer disease is based on the distribution of tau deposition and tracks well with clinical manifestations of the disease (06). McKee and colleagues proposed a similar rating scale for chronic traumatic encephalopathy (37), and studies have demonstrated the utility of the rating scale with the chronic traumatic encephalopathy stage strongly correlating with the degree of cognitive impairment (01). Similar findings have been reported for variants of progressive supranuclear palsy (42). Sakae and colleagues reported increased frontal, temporal, and white matter tau pathology in patients with progressive supranuclear palsy with frontotemporal dementia compared to patients with progressive supranuclear palsy alone (42).

Studies have demonstrated multiple trajectories of tau spread among Alzheimer patients. One group examined 1143 flortaucipir PET images, of which 443 were positive for tau pathology. The distribution of tau pathology fit into four distinct subtypes. A plurality of the PET scans (S1; 32.7%) fit into a limbic-predominant subtype with a Braak-like pattern. Additional subtypes included a parietal-dominant subtype with relative sparing of the medial temporal lobe (S2; 17.8%), a subtype with early occipital lobe involvement (S3; 30.5%), and a subtype with left-sided temporoparietal involvement (S4; 19.0%). Among all these subtypes, phenotypes were consistent with the pattern of tau deposition. For example, S4 patients had the greatest degree of language impairment, whereas S1 patients had the most amnestic impairment. When tracked longitudinally, patients remained within the same subtype. Overall, this study suggests that only about a third of Alzheimer cases progress through the classic Braak pattern of tau progression (55).

It is not entirely clear how aggregated tau inclusions lead to neurodegeneration. It is possible that pathologic tau disrupts axonal transport and the function of cytoplasmic organelles. In aggregated form, tau is unable to perform its usual physiologic function, which could lead to microtubule instability (49). Gomez-Isla and colleagues quantified the neurons, senile plaques, and neurofibrillary tangles in the superior temporal sulcus of patients who had been diagnosed with Alzheimer disease (14). They found a correlation between neurofibrillary tangle burden and neuronal loss but also found that the degree of neuronal loss greatly exceeded neurofibrillary tangle burden. These findings suggest that mechanisms unrelated to neurofibrillary tangles could contribute to cell death.

In the most common tauopathy, Alzheimer disease, amyloid-beta and tau seem to act synergistically to promote neurodegeneration. The relationship of amyloid-beta and tau with respect to Alzheimer pathogenesis was initially explored in 2001 with the publication of a couple of mouse studies. One study found that injecting amyloid-beta fibrils into the murine brain induced a 5-fold increase in local tau tangle formation (15). Another study crossed mice expressing a mutant strain of tau (tauP301L) with a strain of mice overexpressing amyloid precursor protein (APP) (31). The resultant progeny developed an accelerated rate of neurofibrillary tangle formation relative to the parental tauP301L strain. These studies suggest that amyloid-beta plays an upstream role from tau in Alzheimer disease pathogenesis.

Some evidence suggests that tau and amyloid-beta are mutually influential. One study crossed mice expressing mutant APP and presenilin-1 (PS1) with tau knockout mice. Relative to the APP/PS1/tau(+/+) progeny, the APP/PS1/tau(-/-) mice demonstrated roughly a 50% reduction in cortical amyloid plaque burden. These results suggest that, with respect to Alzheimer pathogenesis, amyloid-beta and tau influence one another in a feedback loop (29; 04).

Advanced age is the strongest risk factor for developing sporadic tauopathies. Models of biological aging have provided some insight into how pathogenic tau aggregation could lead to neurodegeneration (19). For example, accumulation of DNA damage is an important driver of biological aging. A drosophila model with impaired DNA damage checkpoints demonstrated an increase in tau-induced cell death and tau neurotoxicity (24). The authors inferred that DNA damage checkpoints play a protective role against the development of tauopathies.

Categorizing the tauopathies. The human brain normally expresses the 3R and 4R isoforms of tau in a 1:1 ratio (16). Although some tauopathies retain an even proportion of 3R and 4R tau, others exhibit aberrations in this ratio. The table below categorizes some of the known tauopathies by whether the pathologic tau is 3R predominant, 4R predominant, or split between 3R and 4R.

3R tauopathies
	• Pick disease
4R tauopathies
	• Argyrophilic grain disease • Corticobasal degeneration • Globular glial tauopathy • Huntington disease • Progressive supranuclear palsy
3R+4R tauopathies
	• Alzheimer disease • Amyotrophic lateral sclerosis / parkinsonism-dementia complex • Chronic traumatic encephalopathy • Down syndrome • Niemann-pick disease, type C • Primary age-related tauopathy
Adapted from (43)

Changes in the ratio of 3R and 4R tau seem to have several adverse effects on neurons. Alterations in 3R and 4R proportions could reduce mitochondrial localization to axons as well as alter axon transport dynamics (48). It is also possible that changes in the isoform proportions alter microtubule binding dynamics; for instance, a study by Lu and Kosik found that 4R tau could displace 3R tau from microtubules (33).

4R tauopathies are more common than 3R tauopathies. The 3R tauopathies include Pick disease, which is characterized by Pick bodies (round, intraneuronal inclusions of tau) that are predominately located in the hippocampus and frontal and temporal cortices.

The 4R tauopathies include progressive supranuclear palsy, in which neurofibrillary tangles, tufted astrocytes, and coiled bodies localize to the pons, subthalamic nucleus, and substantia nigra. In corticobasal degeneration, atrophy occurs in the frontal, parietal, and temporal cortex, along with degeneration of the substantia nigra. Pathology in corticobasal degeneration includes ballooned neurons, astrocytic plaques, coiled bodies, and argyrophilic threads. Another tauopathy, argyrophilic grain disease, is named for one of its pathologic findings; it additionally includes oligodendritic coiled bodies (16).

Tauopathies can additionally be categorized as primary or secondary. In primary tauopathies, tau aggregates are the main driver of neurodegeneration; whereas in secondary tauopathies, other pathologic elements influence tau pathology and neurodegeneration (39). For instance, the most common tauopathy, Alzheimer disease, is a secondary tauopathy in which tau-containing neurofibrillary tangles form in the presence of amyloid plaques (16).

The following table categorizes some of the more commonly encountered tauopathies by whether they are primary or secondary.

Primary tauopathies
	• Argyrophilic grain disease • Corticobasal degeneration • Frontotemporal dementia and parkinsonism linked to chromosome 17 • Pick disease • Progressive supranuclear palsy
Secondary tauopathies
	• Alzheimer disease • Chronic traumatic encephalopathy • Lewy body disorders • Prion disease • TDP-43 mutations associated with semantic dementia
Adapted from (39)

Tau propagation. In some tauopathies, specifically Alzheimer disease and chronic traumatic encephalopathy, the tangles formed by aggregated filaments remain in the extracellular space following the death of the affected cells (32). These “ghost tangles” may contribute to disease propagation throughout the brain by making tau accessible to other cells in the extracellular space. This is likely a critical aspect of the pathophysiology of tauopathies. Braak first identified that tau inclusions originated in the transentorhinal cortex in Alzheimer disease and then spread from there (06). Since then, numerous mouse studies have shown that injection of extracts with mutant tau into wild-type animals causes widespread induction of the pathologic protein into neighboring areas that then degenerated (47). Furthermore, injection into animal models of human brain tissue with different pathologic inclusions consistent with confirmed corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain disease produced lesions in the animal brains demonstrating the same pathologic and phenotypic disease as the respective tauopathy injected (32). This supports the theory of “prion-like” propagation throughout the brain and suggests distinct confirmations of tau for individual diseases (32). The presence of pathologic tau in the extracellular space is also confirmed by the ability to find tau in the cerebrospinal fluid of patients with tauopathies.

Studies have focused on understanding how pathologic tau propagates throughout the brain. Martinez and colleagues focused on aspects of the presynaptic terminal that could promote tau propagation (36). They identified a scaffolding protein of the presynaptic active zone called Bassoon (Bsn), which could help stabilize pathogenic tau seeds. Using mouse models, this group found that downregulating BSN reduced tau propagation and brain atrophy. Additionally, phenotypic effects, such as reduced behavioral impairments, followed the downregulation of Bsn.

Other processes that may be implicated in the pathophysiology of tauopathies include mitopathy and neuroinflammation. Mitopathy is a process that has been implicated in early Alzheimer disease and involves mitochondrial dysfunction and autophagic-lysosomal alterations (22). These processes have been associated in animal studies with tau pathology, but the exact relationship is yet to be understood. Neuroinflammation likely has a contributory role in the neurodegenerative process, with the simultaneous potential to be critically protective and potentially harmful. Supportive of this connection, a study demonstrated colocalization of radiolabeled markers of neuroinflammation and tau pathology in 17 patients with progressive supranuclear palsy (34). Even more compelling was the strong positive correlation between clinical severity and both subcortical neuroinflammation and tau pathology.

Evidence has supported a role for the innate immune system in the development of tauopathies. For example, the “infection hypothesis” of Alzheimer disease posits that immune challenges can provoke neurofibrillary tangle formation (23). One supportive study found evidence that pseudomonas aeruginosa pneumonia precipitates the release of lung endothelial-derived tau, which can ultimately lead to seeding and aggregation of neuronal tau (08). Additional examples of the immune system’s potential involvement in tauopathy pathogenesis include propagation through toll-like receptor signaling, dysregulated complement signaling, and disrupted autophagy of tau (23).

Clinical applications

	• PET scans of radiolabeled ligands to tau serve as in vivo biomarkers for the known tauopathies.
	• Disease-modifying therapies directly targeting the tauopathies have yet to show clinical benefit in clinical trials.
	• Lecanemab, an anti-amyloid drug, has been approved by the FDA for the treatment of Alzheimer disease.

There is a great deal of interest in developing diagnostic tools and treatment for the tauopathies, particularly Alzheimer disease. Developments in the identification and treatment of tauopathies based on the pathologic understanding of the disease are reviewed below.

Biomarkers. For decades, confirmation of tau was limited to autopsy evaluation. In the past few years, PET imaging has emerged as a way to identify tau pathology in vivo by using radiolabeled ligands against neurofibrillary tangles containing tau (35). In Alzheimer disease, the radiolabeled ligand [18F]-AV-1451 or flortaucipir was shown to successfully identify tau distribution in patients compared to healthy controls, likely due to binding to the paired helical conformation of tau in Alzheimer disease brains. Yet in other tauopathies, the data for flortaucipir to identify tau in the expected areas have been variable, and off-target binding may limit its utility in chronic traumatic encephalopathy and other disorders.

Several other ligands have also been created, and in mild traumatic brain injury and chronic traumatic encephalopathy, promising results suggest that tau can be successfully imaged in vivo. One such ligand, 11C-pyridinyl-butadienyl-benzothiazole 3 (11C-PBB3), was able to identify tau deposits in Alzheimer disease and non-Alzheimer disease tauopathies. This ligand also demonstrated increased MAPT-PET binding in the neocortical grey and white matter in patients with late-onset neuropsychiatric symptoms following traumatic brain injury (50). One small study examined patients at risk for chronic traumatic encephalopathy and was able to demonstrate a tau-PET binding profile consistent with later-stage chronic traumatic encephalopathy in patients who were negative for amyloid-PET binding (30). The authors concluded that MAPT-PET binding may represent a useful biomarker for chronic traumatic encephalopathy, but it is currently only for later-stage disease. Similar results were shown in patients with progressive supranuclear palsy who demonstrated increased tau-PET binding in the globus pallidus and putamen relative to age-matched healthy controls (45). There was, however, a positive correlation between tau-PET binding and age within both groups, which may challenge the application and clinical utility of this technology as a diagnostic tool.

Extracellular tau as measured in cerebrospinal fluid is currently used to help diagnose Alzheimer disease. A standard Alzheimer diagnostic panel includes the biomarkers amyloid-beta42, total tau, and hyperphosphorylated tau (p-tau). When detecting incipient Alzheimer disease in patients with mild cognitive impairment, combinations of these three biomarkers yielded sensitivities of 95% and specificities of 80% to 90% (18). Research identifying fluid biomarkers for tauopathies other than Alzheimer disease is ongoing. One study focused on microtubule-binding region tau (MTBR-tau275 and MTBR-tau282). This tau species showed an increase in the brains of patients with primary tauopathies, especially corticobasal degeneration and FTLD-MAPT. Concurrently, concentrations of these tau species demonstrated a proportional decrease in the CSF of these patients. MTBR-tau275 and MTBR-tau282 show promise as biomarkers for tauopathies other than Alzheimer disease (20).

Skin biopsy has been utilized to detect peripheral alpha-synuclein and help diagnose alpha-synucleinopathies, such as Parkinson disease. A study evaluated whether skin biopsy might have diagnostic utility for tauopathies (53). The researchers examined tau expression in the skin biopsies of patients clinically diagnosed with progressive supranuclear palsy and corticobasal degeneration. This was compared with the tau expression in the skin biopsies of patients with the alpha-synucleinopathies Parkinson disease and multiple system atrophy. The authors found that tau is highly expressed in the nerve fibers surrounding dermal autonomic structures and that there was a significantly increased amount of tau in progressive supranuclear palsy/corticobasal degeneration biopsies relative to Parkinson disease/multiple system atrophy biopsies. These findings suggest that skin biopsy may have utility for diagnosing tauopathies.

Disease-modifying therapies. Given the strong association between tau deposition, cellular toxicity, and neurodegeneration, tau is an obvious target for potential disease-modifying therapies. Active and passive antibody-based clinical trials are underway or have been completed for Alzheimer disease. A humanized monoclonal antibody against tau, ABBV-8E12, was well tolerated without severe adverse effects in a stage 1 trial (57); however, this drug failed to demonstrate efficacy in patients with early Alzheimer disease (11). In a similar vein, a drug targeting progressive supranuclear palsy was well tolerated (05) but failed to prove efficacious in a phase 2 clinical trial (09). Many treatment approaches that have shown promise in animal models of tauopathies have failed to prove to be safe and effective in human clinical trials. The vast majority of these trials are in Alzheimer disease and target microtubule stabilization, prevention of tau hyperphosphorylation, and reduction of tau aggregates. Valproic acid, lithium, methylene blue, and naproxen failed to show cognitive improvement in randomized trials (03; 46). Although tau is an appealing and potentially promising target for disease-modifying therapy, more research is needed to find a safe treatment that slows cognitive decline in tauopathies.

Studies continue to identify potential targets for disease-modifying therapy against tauopathies. A 2023 study identified 82 genetic regulators of tau protein levels. Using mouse tauopathy models, they found that knockdown of three of these genes (USP7, RNF130, and RNF149), which function through the C terminus of Hsc70-interacting protein, reduced pathologic tau levels and improved learning and memory deficits (26). Another study examined tetrandrine, which is thought to correct the lysosomal alkalinization that impairs the autophagy-lysosomal pathway (ALP) (51). The ALP is important for the degradation of hyperphosphorylated tau. The researchers found that, in a mouse model, tetrandrine enhanced tau neurofibrillary tangle clearance and improved memory in a dose-dependent manner. In another study, researchers generated two D-enantiomeric peptides that bind tau with a high affinity (02). In vitro, these ligands inhibit the formation of tau aggregates by stabilizing tau in its nontoxic monomeric form.

In 2023, the U.S. Food and Drug Administration approved one of the first disease-modifying therapies for Alzheimer disease, lecanemab (U.S. Food and Drug Administration 2023). This monoclonal antibody removes amyloid via binding to soluble amyloid-beta protofibrils. In a phase 3 clinical trial (Clarity AD), patients receiving lecanemab declined 1.21 points on the Clinical Dementia Rating-Sum of Boxes (CDR-SB, the primary endpoint), versus a decline of 1.66 points in the placebo group (p< 0.001) (54). Lecanemab also significantly reduced brain amyloid burden. Over the 18 months, CSF T-tau and P-tau181 steadily increased in the placebo group, whereas these biomarkers decreased in the lecanemab group. Another anti-amyloid drug, donanemab, demonstrated promising results in an 18-month phase 3 trial (44). Alzheimer drugs targeting tau remain in development. A phase 1b trial evaluating an anti-tau drug, BIIB080, found that this treatment significantly reduced tau burden (as measured by CSF and PET) among the 46 mild Alzheimer patients over 36 weeks (10). BIIB080’s effect on clinical outcomes will be evaluated in an ongoing phase 2 trial.

Overall, the substantial interest in tauopathy research continues to promote the emergence of promising new therapies.

References

01: Alosco ML, Cherry JD, Huber BR, et al. Characterizing tau deposition in chronic traumatic encephalopathy (CTE): utility of the McKee CTE staging scheme. Acta Neuropathol 2020;140(4):495-512. PMID 32778942
02: Altendorf T, Gering I, Santiago-Schubel B, et al. Stabilization of monomeric tau protein by all D-enantiomeric peptide ligands as therapeutic strategy for Alzheimer’s disease and other tauopathies. Int J Mol Sci 2023;24(3):2161. PMID 36768484
03: Aprahamian I, Stella F, Forlenza OV. New treatment strategies for Alzheimer’s disease: is there a hope? Indian J Med Res 2013;138(4):449-60. PMID 24434253
04: Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer’s disease pathogenesis. JAMA Neurol 2014;71(4):505-8. PMID 24493463
05: Boxer AL, Qureshi I, Ahlijanian M, et al. Safety of the tau-directed monoclonal antibody BIIB092 in progressive supranuclear palsy: a randomised, placebo-controlled, multiple ascending dose phase 1b trial. Lancet Neurol 2019;18(6):549-58. PMID 31122495
06: Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82(4):239-59. PMID 1759558
07: Buee L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 2000;33(1):95-130. PMID 10967355
08: Choi CS, Gwin M, Voth S, et al. Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy. J Biol Chem 2022;298(1):101482. PMID 34896150
09: Dam T, Boxer AL, Golbe LI, et al. Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial. Nat Med 2021;27(8):1451-7. PMID 34385707
10: Edwards AL, Collins JA, Junge C, et al. Exploratory tau biomarker results from a multiple ascending-dose study of BIIB080 in Alzheimer disease: a randomized clinical trial. JAMA Neurol 2023;80(12):1344-52. PMID 37902726
11: Florian H, Wang D, Arnold SE, et al. Tilavonemab in early Alzheimer’s disease: results from a phase 2, randomized, double-blind study. Brain 2023;146(6):2275-84. PMID 36730056
12: Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M. Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 2015;41(1):24-46. PMID 25556536
13: Goedert M. Oskar Fischer and the study of dementia. Brain 2009;132(Pt 4):1102-11. PMID 18952676
14: Gomez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1997;41(1):17-24. PMID 9005861
15: Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001;293(5534):1491-5. PMID 11520988
16: Gotz J, Halliday G, Nisbet RM. Molecular pathogenesis of the tauopathies. Annu Rev Pathol 2019;14:239-61.** PMID 30355155
17: Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986;83(13):4913-7. PMID 3088567
18: Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow PK, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5(3):228-34. PMID 16488378
19: Han ZZ, Fleet A, Larrieu D. Can accelerated aging models inform us on age-related tauopathies? Aging Cell 2023;22(5):e13830. PMID 37013265
20: Horie K, Barthelemy NR, Spina S, et al. CSF tau microtubule-binding region identifies pathological changes in primary tauopathies. Nat Med 2022;28(12):2547-54. PMID 36424467
21: Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702-5. PMID 9641683
22: Hou X, Watzlawik JO, Cook C, et al. Mitophagy alterations in Alzheimer’s disease are associated with granulovacuolar degeneration and early tau pathology. Alzheimers Dement 2020;17(3):417-30. PMID 33090691
23: Johnson AM, Lukens JR. The innate immune response in tauopathies. Eur J Immonol 2023;53(6):2250266. PMID 36932726
24: Khurana V, Merlo P, DuBoff B, et al. A neuroprotective role for the DNA damage checkpoint in tauopathy. Aging Cell 2012;11(2):360-2. PMID 22181010
25: Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 1963;197:192-3. PMID 14032480
26: Kim J, de Haro M, Al-Ramahi I, et al. Evolutionary conserved regulators of tau identify targets for new therapies. Neuron 2023;111(6):824-38.e7. PMID 36610398
27: Koga S, Parks A, Kasanuki K, et al. Cognitive impairment in progressive supranuclear palsy is associated with tau burden. Mov Disord 2017;32(12):1772-9. PMID 29082658
28: Kovacs GG. Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 2015;41(1):3-23. PMID 25495175
29: Leroy K, Ando K, Laporte V, et al. Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1mice. Am J Pathol 2012;181(6):1928-40. PMID 23026200
30: Lesman-Segev OH, La Joie R, Stephens ML, et al. Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy. Neuroimage Clin 2019;24:102025. PMID 31670152
31: Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293(5534):1487-91. PMID 11520987
32: Ling H. Untangling the tauopathies: current concepts of tau pathology and neurodegeneration. Parkinsonism Relat Disord 2018;46 Suppl 1:S34-8. PMID 28789904
33: Lu M, Kosik KS. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol Biol Cell 2001;12(1):171-84. PMID 11160831
34: Malpetti M, Passamonti L, Ritman T, et al. Neuroinflammation and tau colocalize in vivo in progressive supranuclear palsy. Ann Neurol 2020;88(6):1194-204. PMID 32951237
35: Marquie M, Aguero C, Amaral AC, et al. [18F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series. Acta Neuropathol Commun 2019;7(1):164. PMID 31661038
36: Martinez P, Patel H, You Y, et al. Bassoon contributes to tau-seed propagation and neurotoxicity. Nature Neurosci 2022;25(12):1597-607. PMID 36344699
37: McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013;136(Pt 1):43-64. PMID 23208308
38: Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010;67:953-66. PMID 20869593
39: Montalto G, Ricciarelli R. Tau, tau kinases, and tauopathies: an updated overview. BioFactors 2023;49:502-11. PMID 36688478
40: Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43(6):815-25. PMID 9629852
41: Rawat P, Sehar U, Bisht J, Selman A, Culberson J, Reddy PH. Phosphorylated tau in Alzheimer’s disease and other tauopathies. Int J Mol Sci 2022;23(21):12841. PMID 36361631
42: Sakae N, Josephs KA, Litvan I, et al. Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy. Mov Disord 2019;34(11):108-14. PMID 31433871
43: Sexton C, Snyder H, Beher D, et al. Current directions in tau research: highlights from tau 2020. Alzheimers Dement 2022;18(5):988-1007.** PMID 34581500
44: Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ2 randomized clinical trial. JAMA 2023;330(6):512-27. PMID 37459141
45: Smith R, Schain M, Nilsson C, et al. Increased basal ganglia binding of 18 F-AV-1451 in patients with progressive supranuclear palsy. Mov Disord 2017;32(1):108-14. PMID 27709757
46: Soeda Y, Saito M, Maeda S, et al. Methylene blue inhibits formation of tau fibrils but not of granular tau oligomers: a plausible key to understanding failure of a clinical trial for Alzheimer’s disease. J Alzheimers Dis 2019;68(4):1677-86. PMID 30909223
47: Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol 2013;12(6):609-22. PMID 23684085
48: Stoothoff W, Jones PB, Spires-Jones TL, et al. Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J Neurochem 2009;111(2):417-27. PMID 19686388
49: Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest 2019;99(7):912-28.** PMID 30742061
50: Takahata K, Kimura Y, Sahara N, et al. PET-detectable tau pathology correlates with long-term neuropsychiatric outcomes in patients with traumatic brain injury. Brain 2019;142(10):3265-79. PMID 31504227
51: Tong BC, Huang AS, Wu AJ, et al. Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies. J Biomed Sci 2022;29(1):85. PMID 36273169
52: U.S. Food and Drug Administration. FDA converts novel Alzheimer’s disease treatment to traditional approval. Available from: https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval. Accessed 2023.
53: Vacchi E, Lazzarini E, Pinton S, et al. Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies. Brain 2022;145(8):2755-68. PMID 35485527
54: Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023;388(1):9-21. PMID 36449413
55: Vogel JW, Young AL, Oxtoby NP, et al. Four distinct trajectories of tau deposition identified in Alzheimer’s disease. Nat Med 2021;27(5):871-81.** PMID 33927414
56: Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72(5):1858-62. PMID 1057175
57: West T, Hu Y, Verghese PB, et al. Preclinical and clinical development of ABBV-8E12, a humanized anti-tau antibody, for treatment of Alzheimer’s disease and other tauopathies. J Prev Alzheimers Dis 2017;4(4):236-41. PMID 29181488
58: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Hannah Noah MD MPH

Dr. Noah of Boston University has no relevant financial relationships to disclose.
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Andrew E Budson MD

Dr. Budson of the Boston VA Healthcare System and Boston University School of Medicine received honorariums from AbbVie and Eli Lilly as a consultant and grant support from Bristol Meyers Squibb and VoxNeuro as principal investigator.
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Editor

Howard S Kirshner MD

Dr. Kirshner of Vanderbilt University School of Medicine has no relevant financial relationships to disclose.
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Stephanie Bissonnette MPH DO
Andrew Ferree MD PhD

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Pathogenesis and pathology of tauopathies

Also Relevant

Alzheimer disease
Chronic traumatic encephalopathy
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Memory loss
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Neurobehavioral & Cognitive Disorders

Pathogenesis and pathology of tauopathies …

Pathogenesis and pathology of tauopathies

Introduction

Overview

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Historical note and terminology

Description

Clinical applications

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Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

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Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

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Pathogenesis and pathology of tauopathies

Introduction

Overview

Key points

Historical note and terminology

Description

Clinical applications

References

Contributors

Authors

Editor

Former Authors

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

Anti-LGI1 encephalitis

This is an article preview.
Start a Free Account
to access the full version.