What is Tau Pathology?

Tau protein changes, known as tau pathology, are a key feature of Alzheimer’s disease (AD) and similar brain conditions. The main cause of this change is something called "hyperphosphorylation," where tau proteins gain extra chemical groups, causing them to misbehave. In their normal state, tau proteins help build and stabilize the microtubules, which are structures that keep brain cells organized and transport important materials. But when tau becomes hyperphosphorylated, it not only loses this stabilizing function but also becomes toxic. It begins to trap healthy tau proteins and other essential proteins that support microtubules, disrupting the cell's internal structure and causing damage. This breakdown is thought to contribute significantly to the brain cell death seen in Alzheimer’s and related diseases.1

Role of Tau Pathology in Early-Stage AD diagnosis

Tau pathology plays a significant role in diagnosing early-stage Alzheimer's disease (AD) due to its strong link with symptom development and progression.2 In AD, abnormal tau proteins begin to accumulate and form neurofibrillary tangles, disrupting essential brain cell functions and causing cognitive decline. Identifying tau pathology, especially through imaging and biomarkers, can help distinguish AD from other neurodegenerative diseases and predict the onset of symptoms, making it a valuable marker in early diagnosis.2

Increased focus on tau targeted treatments for AD has necessitated the requirement for specific biomarkers for detecting insoluble, aggregated tau.3 Tau positron emission tomography (PET) imaging studies have shown that insoluble tau aggregates are predictive of cognitive decline, even in the early pre-symptomatic stages of AD.4 Tau PET is currently the most accurate prognostic marker for AD. However, the high cost and complex infrastructure required for tau PET imaging limit its use to specialized centers.5

Fortunately, recent advancements in blood-based biomarkers have provided a more cost-effective and clinically accessible option to testing. The most common biomarkers of tau include mid-domain total tau or phosphorylated tau (pTau) such as pTau181, pTau217, or pTau231.6-9 However, these biomarkers are more strongly associated with beta-amyloid plaque rather than insoluble tau aggregates.

Difference between measuring active Tau Pathology and pTau217

AD is the most prevalent tauopathy and is classified as a secondary tauopathy due to the association of tau pathology with amyloidosis.10 A diagnosis of AD requires a high density of both neurofibrillary tangles made of hyperphosphorylated tau and neuritic plaques of beta-amyloid. However, it has been established that tau pathology correlates more strongly with AD cognitive impairment than amyloidosis.2,11 In fact, as much ~30% of normal aged individuals have as many beta-amyloid plaques in their brains as a typical case of AD.12 Moreover, recent data suggests that as many as 12% of pTau217 tests yield an indeterminant result, also known as “the grey zone” and therefore require additional testing.13,14 Since pTau217 assay is a measure of beta-amyloid pathology, this means it can have up to 29% false positive results in presymptomatic test cases.15 As such, unlike pTau217 assays, measuring active tau pathology may predict cognitive impairment and replace tau PET which is invasive, expensive and offers limited availability.16

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  1. Iqbal K, Alonso Adel C, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005;1739(2-3):198-210. doi:10.1016/j.bbadis.2004.09.008. https://pubmed.ncbi.nlm.nih.gov/15615638/

  2. Frontzkowski, L., Ewers, M., Brendel, M. et al. Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading. Nat Commun 13, 4899 (2022). https://doi.org/10.1038/s41467-022-32592-7 https://www.nature.com/articles/s41467-022-32592-7

  3. Ossenkoppele R, van der Kant R, Hansson O. Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials. Lancet Neurol. 2022;21(8):726-734. doi:10.1016/S1474-4422(22)00168-5 https://pubmed.ncbi.nlm.nih.gov/35643092/

  4. Ossenkoppele, R., Pichet Binette, A., Groot, C. et al. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med28, 2381–2387 (2022). https://doi.org/10.1038/s41591-022-02049-x https://www.nature.com/articles/s41591-022-02049-x

  5. Smith R, Cullen NC, Pichet Binette A, et al. Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients. Alzheimers Dement. 2023;19(6):2497-2507. doi:10.1002/alz.12875 https://pubmed.ncbi.nlm.nih.gov/36516028/

  6. Sato C, Barthélemy NR, Mawuenyega KG, et al. Tau Kinetics in Neurons and the Human Central Nervous System [published correction appears in Neuron. 2018 May 16;98(4):861-864. doi: 10.1016/j.neuron.2018.04.035]. Neuron. 2018;97(6):1284-1298.e7. doi:10.1016/j.neuron.2018.02.015 https://pmc.ncbi.nlm.nih.gov/articles/PMC6137722/

  7. Cicognola C, Brinkmalm G, Wahlgren J, et al. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease. Acta Neuropathol. 2019;137(2):279-296. doi:10.1007/s00401-018-1948-2 https://pubmed.ncbi.nlm.nih.gov/30547227/

  8. Barthélemy, N. R., Horie, K., Sato, C. & Bateman, R. J. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J. Exp. Med. (2020). https://rupress.org/jem/article/217/11/e20200861/151982/Blood-plasma-phosphorylated-tau-isoforms-track-CNS

  9. Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021;141(5):709-724. doi:10.1007/s00401-021-02275-6 https://pubmed.ncbi.nlm.nih.gov/33585983/

  10. Kyalu Ngoie Zola, N., Balty, C., Pyr dit Ruys, S. et al. Specific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies. Nat Commun 14, 3706 (2023). https://www.nature.com/articles/s41467-023-39328-1

  11. Iqbal K, Liu F, Gong CX. Alzheimer disease therapeutics: focus on the disease and not just plaques and tangles. Biochem Pharmacol. 2014;88(4):631-639. doi:10.1016/j.bcp.2014.01.002 https://pmc.ncbi.nlm.nih.gov/articles/PMC4024824/

  12. Morris GP, Clark IA, Vissel B. Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathol. 2018;136(5):663-689. doi:10.1007/s00401-018-1918-8 https://pubmed.ncbi.nlm.nih.gov/30349969/

  13. Howe MD, Britton KJ, Joyce HE, et al. Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease. Alzheimers Res Ther. 2024;16(1):154. Published 2024 Jul 6. doi:10.1186/s13195-024-01521-9 https://pmc.ncbi.nlm.nih.gov/articles/PMC11227160/

  14. Arranz J, Zhu N, Rubio-Guerra S, et al. Diagnostic performance of plasma pTau 217, pTau 181, Aβ 1-42 and Aβ 1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease. Preprint. Res Sq. 2023;rs.3.rs-3725688. Published 2023 Dec 13. doi:10.21203/rs.3.rs-3725688/v1 https://pmc.ncbi.nlm.nih.gov/articles/PMC10760237/

  15. https://pennmemorycenter.org/new-ad-blood-test/#:~:text=Yet%2C%20there%20is%20not%20sufficient,incorrectly%20categorizes%20results%20as%20true

  16. Groot C, et al. Tau Positron Emission Tomography for Predicting Dementia in Individuals with Mild Cognitive Impairment. JAMA Neurol. 2024;81(8):845–856. https://jamanetwork.com/journals/jamaneurology/fullarticle/2819811