Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease

Overview

Journal Ann Neurol

Specialty Neurology

Date 2023 Feb 27

PMID 36843330

Authors

Kanta Horie

Yan Li

Nicolas R Barthelemy

Brian Gordon

Jason Hassenstab

Tammie L S Benzinger

Anne M Fagan

John C Morris

Celeste M Karch

Chengjie Xiong

Ricardo Allegri

Patricio Chrem Mendez

Takeshi Ikeuchi

Kensaku Kasuga

James Noble

Martin Farlow

Jasmeer Chhatwal

Gregory Day

Peter R Schofield

Colin L Masters

Johannes Levin

Mathias Jucker

Jae-Hong Lee

Jee Hoon Roh

Chihiro Sato

Pallavi Sachdev

Akihiko Koyama

Larisa Reyderman

Randall J Bateman

Eric McDade

Affiliations

Soon will be listed here.

Abstract

Objective: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms.

Methods: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy.

Results: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs.

Interpretation: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.

Citing Articles

Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers.

Kimura T, Sato H, Kano M, Tatsumi L, Tomita T FEBS Open Bio. 2023; 14(2):181-193.

PMID: 37391389 PMC: 10839341. DOI: 10.1002/2211-5463.13667.

References

Dam T, Boxer A, Golbe L, Hoglinger G, Morris H, Litvan I . 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):1451-1457. DOI: 10.1038/s41591-021-01455-x. View

Croft C, Goodwin M, Ryu D, Lessard C, Tejeda G, Marrero M . Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions. Acta Neuropathol. 2021; 141(3):359-381. PMC: 7882582. DOI: 10.1007/s00401-021-02264-9. View

von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow E, Mandelkow E . Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000; 97(10):5129-34. PMC: 25793. DOI: 10.1073/pnas.97.10.5129. View

Braak H, Braak E . Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995; 16(3):271-8; discussion 278-84. DOI: 10.1016/0197-4580(95)00021-6. View

Ryman D, Acosta-Baena N, Aisen P, Bird T, Danek A, Fox N . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014; 83(3):253-60. PMC: 4117367. DOI: 10.1212/WNL.0000000000000596. View

Thijssen E, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L . Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. 2020; 26(3):387-397. PMC: 7101073. DOI: 10.1038/s41591-020-0762-2. View

La Joie R, Visani A, Baker S, Brown J, Bourakova V, Cha J . Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020; 12(524). PMC: 7035952. DOI: 10.1126/scitranslmed.aau5732. View

Su Y, Blazey T, Snyder A, Raichle M, Marcus D, Ances B . Partial volume correction in quantitative amyloid imaging. Neuroimage. 2014; 107:55-64. PMC: 4300252. DOI: 10.1016/j.neuroimage.2014.11.058. View

Cherry J, Esnault C, Baucom Z, Tripodis Y, Huber B, Alvarez V . Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer's disease. Acta Neuropathol Commun. 2021; 9(1):86. PMC: 8114683. DOI: 10.1186/s40478-021-01189-4. View

10.

Barthelemy N, Horie K, Sato C, Bateman R . Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease. J Exp Med. 2020; 217(11). PMC: 7596823. DOI: 10.1084/jem.20200861. View

11.

Kaeser S, Hasler L, Lambert M, Bergmann C, Bottelbergs A, Theunis C . CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles. Acta Neuropathol. 2021; 143(2):287-290. PMC: 8742811. DOI: 10.1007/s00401-021-02400-5. View

12.

Novak P, Kovacech B, Katina S, Schmidt R, Scheltens P, Kontsekova E . ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer's disease. Nat Aging. 2023; 1(6):521-534. DOI: 10.1038/s43587-021-00070-2. View

13.

Fitzpatrick A, Falcon B, He S, Murzin A, Murshudov G, Garringer H . Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017; 547(7662):185-190. PMC: 5552202. DOI: 10.1038/nature23002. View

14.

Nelson P, Alafuzoff I, Bigio E, Bouras C, Braak H, Cairns N . Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012; 71(5):362-81. PMC: 3560290. DOI: 10.1097/NEN.0b013e31825018f7. View

15.

Palmqvist S, Janelidze S, Quiroz Y, Zetterberg H, Lopera F, Stomrud E . Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020; 324(8):772-781. PMC: 7388060. DOI: 10.1001/jama.2020.12134. View

16.

Horie K, Barthelemy N, Sato C, Bateman R . CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain. 2020; 144(2):515-527. PMC: 7940175. DOI: 10.1093/brain/awaa373. View

17.

Mila-Aloma M, Ashton N, Shekari M, Salvado G, Ortiz-Romero P, Montoliu-Gaya L . Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease. Nat Med. 2022; 28(9):1797-1801. PMC: 9499867. DOI: 10.1038/s41591-022-01925-w. View

18.

Roberts M, Sevastou I, Imaizumi Y, Mistry K, Talma S, Dey M . Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2020; 8(1):13. PMC: 7001291. DOI: 10.1186/s40478-020-0884-2. View

19.

Horie K, Barthelemy N, Mallipeddi N, Li Y, Franklin E, Perrin R . Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain. Acta Neuropathol Commun. 2020; 8(1):149. PMC: 7450927. DOI: 10.1186/s40478-020-01019-z. View

20.

Kadavath H, Hofele R, Biernat J, Kumar S, Tepper K, Urlaub H . Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci U S A. 2015; 112(24):7501-6. PMC: 4475932. DOI: 10.1073/pnas.1504081112. View