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Randomized Controlled Trial
. 2025 Sep;21(9):e70689.
doi: 10.1002/alz.70689.

The relationship of soluble tau species with Alzheimer's disease amyloid plaque removal and tau pathology

Eric M McDade  1 , Nicolas R Barthélemy  1 , Guoqiao Wang  1 , Yan Li  1 , Yuchen Cao  1 , Brian Gordon  1 , Tammie L S Benzinger  1 , David Clifford  1 , Alison M Goate  2 , Alan E Renton  2 , Jason Hassenstab  1 , Jorge J Llibre-Guerra  1 , Richard J Perrin  1   3 , Chengjie Xiong  4 , Carlos Cruchaga  5 , Catherine J Mummery  6 , Sarah B Berman  7 , James Lah  8 , Erik D Roberson  9 , Christopher Van Dyck  10 , Serge Gauthier  11 , Colin L Masters  12 , Mario Masellis  13 , Tobias Bittner  14 , Roy Yaari  15 , Jasmeer Chhatwal  16 , Patricio Chrem  17 , William Brooks  18 , Kazushi Suzuki  19 , Johannes J Levin  20 , Mathias Jucker  21 , John Ringman  22 , David Wallon  23 , Takeshi Ikeuchi  24 , Jae-Hong Lee  25 , Jee Hoon Roh  26 , Peter Schofield  18 , Nick C Fox  6 , Natalie S Ryan  6 , Jonathan Vöglein  20 , Celeste Karch  5 , Laura Ibáñez  1   5 , Gregory S Day  27 , Raquel Sánchez-Valle  28 , Alisha Daniels  1 , John C Morris  1 , Charlene Supnet-Bell  1 , Allan I Levey  8 , Randall J Bateman  1 ; DIAN‐TU Study Team and DIAN Obs Team
Affiliations
Randomized Controlled Trial

The relationship of soluble tau species with Alzheimer's disease amyloid plaque removal and tau pathology

Eric M McDade et al. Alzheimers Dement. 2025 Sep.

Abstract

Background: Tau-derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid-beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long-term anti-Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them.

Methods: A post-hoc analysis of the DIAN-TU-001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab (n = 50), gantenerumab (n = 52), or placebo (n = 40). High-resolution mass spectrometry quantified CSF tau species over four years.

Results: Phosphorylated tau (p-tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab-mediated Aβ plaque reduction. Nearly a decade later, MTBR-tau243 and p-tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression.

Discussion: Initially changing soluble p-tau species track Aβ plaque reduction, while ptau205 and MTBR-243 reflect tau tangle pathology, informing different pathways of therapeutic strategies.

Highlights: p-tau217 and p-tau231 correlate with Aβ-PET and respond to Aβ-plaque lowering therapies. Aβ immunotherapy trials support a direct link between p-tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT-related biomarkers. Blood-based p-tau217 assays may provide a non-invasive tool to monitor Aβ therapies. MTBR-tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT-targeting therapies.

Keywords: amyloid beta plaque reduction; dominantly inherited Alzheimer's disease; microtubule‐binding region; phosphorylated tau.

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Conflict of interest statement

There are several inventions that have been filed by Washington University for patents, including “Methods of diagnosing AD with phosphorylation changes” and “Methods to detect MTBR‐tau isoforms and use”. These intellectual properties owned by Washington University can be or are licensed and some licensing income may be distributed to Drs. Barthelemy, Bateman, McDade and other inventors. These intellectual properties being licensed by Washington University from C2N and currently being utilized in our research have been reviewed by the Washington University COI and ICOI committees.

All co‐inventors, including some lab members, the University, and Drs. Barthélemy, Bateman, McDade could receive part of the profits from any sales of these tests by C2N, which is in the process of licensing or has licensed some IP from the University. These activities have been reviewed by Washington University's (WU) Conflicts of Interest Review Committee in accordance with WU's Research Conflicts of Interest Policy and WU's Institutional Conflict of Interest Review Committee in accordance with WU's Institutional Conflict of Interest Policy.

EMM is supported by funding from the National Institute on Aging (K23AG046363; U01AG059798), the Anonymous Foundation, GHR, the Alzheimer's Association, and institutional support. Additional research support (to the institution) was provided by Eli Lilly, Eisai, Hoffmann‐La Roche, and the DIAN‐TU Pharma Consortium. He has participated in speaker engagements for Eisai, Neurology Live, and Projects in Knowledge‐Kaplan. Advisory board roles, consulting, and Data Safety Monitoring Board (DSMB) participation have included relationships with Eli Lilly, Alnylam, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann‐La Roche, Grifols, and Merck.

YL is the co‐inventor of the technology “Novel Tau isoforms to predict onset of symptoms and dementia in Alzheimer disease” which is in the process of licensing by C2N. She may receive royalties related to the licensing agreement.

NCF reports consulting fees from Biogen, Eisai, Ionis, Lilly, Roche, and Siemens – all paid to UCL; he has served on a Data Safety Monitoring Board for Biogen; he acknowledges grant support from the Alzheimer Society, Alzheimer Research UK, Rosetrees Trust, the Sigrid Rausing Trust, the UK Dementia Research Institute and the UK NIHR UCLH Biomedical Research Centre.

AER has received funding from National Institute on Aging, National Institute of Neurological Disorders and Stroke, Alzheimer Association, JPB Foundation, and Donors Cure.

RJ P reports no competing interests directly relevant to this work.

JV served as a consultant for Lilly and Eisai, and received coverage for conference and travel expenses from Biogen, Eisai, the Alzheimer's Association, the Austrian Alzheimer's Society and the German Society of Nuclear Medicine.

GSD reports no competing interests directly relevant to this work. His research is supported by NIH (K23AG064029, U01AG057195, U01NS120901, U19AG032438). He serves as a consultant for Parabon Nanolabs Inc and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is the co‐Project PI for a clinical trial in anti‐NMDAR encephalitis, which receives support from NINDS (U01NS120901) and Amgen Pharmaceuticals; and a consultant for Arialys Therapeutics. He has developed educational materials for Continuing Education Inc and Ionis Pharmaceutical. He owns stock in ANI pharmaceuticals. Dr. Day's institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in‐kind contributions of radiotracer precursors for tau‐PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly).

JR reports no competing interests.

KS reports no competing interests.

WB reports no competing interests.

SB reports no competing interests.

TI reports no competing interests

CHvD is a consultant for Eisai, Roche, BMS, Ono, and Cerevel and receives grant support for clinical trials from Eisai, Biogen, Eli Lilly, UCB, Cerevel, Janssen, Roche, and Genentech.

JJL reports no competing interests.

CX reports no competing interests.

BG reports no competing interests.

DW reports no competing interests.

PRS reports no competing interests.

MJ reports no competing interests.

JHL reports no competing interests.

JHR reports no competing interests.

JC has served on a medical advisory board for MEDACorp

RY full time employee and minor shareholder of Eli Lilly and Co.

TB is a full time employee and shareholder of F.Hoffmann‐LaRoche

TLSB has received grants or contracts from Siemens paid to her institution; consulting fees from Biogen** ($5,000‐10,000), Eli Lilly, Eisai** ($5,000‐10,000), Bristol Myers Squibb, J&J, and Merck; payment for CME activity from Medscape, PeerView, and Neurology Today; and travel reimbursement from Cedars Sinai Medical Center, Hong Kong Neurological Association and the Alzheimer's Association. She reports the following patents planned, issued or pending: US patent 16/097, 457 (DIFFUSION BASIS SPECTRUM IMAGING (DBSI), A NOVEL DIFFUSION MRI METHOD USED TO QUANTIFY NEUROINFLAMMATION AND PREDICT ALZHEIMER'S DISEASE (AD) PROGRESSION), and US Patent 12,016,701 (Quantitative Differentiation of Tumor Heterogeneity Using Diffusion MR Imaging Data). She has participated in a Data Safety Monitoring Board or Advisory Board of Siemens and served as an external advisor for NIH‐funded studies (no payments). She has served as the co‐chair of ASNR Alzheimer's, ARIA and Dementia Study Group, and RSNA Quantitative Imaging Committee (QuIC) (all unpaid). She has served as a committee member of the American College of Radiology/ALZ NET imaging, NIH CNN Study Section Chair, and had a leadership or fiduciary role in the ACR Commission on Neurology (all unpaid). She has received technology transfer and precursors for radiopharmaceuticals from Avid Radiopharmaceuticals/Eli Lilly, LMI, and Lantheus, as well as a scanner loan from Hyperfine to her institution.

CK reports research support from Eisai.

AL co‐founder EmTherapo; consulting and advisory board Cognition Therapeutics, NextSense, Cognito Therapeutics, MEPSGEN.

CC has received research support from: GSK and EISAI. CC is a member of the scientific advisory board of Circular Genomics and owns stocks. CC is a member of the scientific advisory board of ADmit.

JL reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve, Merck and Roche, consulting fees from Axon Neuroscience, EISAI and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4‐Repeat Tauopathies” (PCT/EP2024/053388) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work.

AG reports serving on Scientific Advisory Boards for: Genentech and Muna Therapeutics and as a consultant for: Merck, Biogen and Voyager Therapeutics. She reports royalties for: Taconic Biosciences, Athena Diagnostics

GW reports serving on a Data Safety Committee for Eli Lilly and Company and statistical consultant for Eisai inc. and Alector Inc.

MM reports no competing interests.

LI reports no competing interests.

NR reports no competing interests.

RSV has served in Advisory boards Meetings for Wave Life Sciences, Ionis, UCB, Prevail, Pfizer and Novo Nordisk and received personal fees for participating in educational activities from Roche Diagnostics and Neuroxpharma.

EDR Is an advisor for AGTC, DMC for Lilly, royalties on licensing to Genentech, owner of additional IP related to tau.

PCM reports no competing interests.

CJM reports advisory board/consultancy at Biogen, Roche, Wave, Ionis, Prevail, Lilly and Eisai; Grant for BRAPIDD ultrafast MRI study Biogen; Speaker for sponsored events/honoraria from Biogen, Roche, Eisai, Ionis and Lilly.

SG reports activity as a scientific advisor to Alzheon, AmyriAD, Eisai Canada, Lilly Canada, NovoNordisk Canada, Enigma USA.

JCM reports no competing interests.

DBC is Co‐Medical Director of DIAN–TU. He receives royalties from Wolters Kluwer. He serves as scientific consultant to F. Hoffmann‐La Roche Ltd/Genentech, Wave Life Sciences, Excision BioTherapeutics, Atara Biotherapeutics Inc, Sanofi Genzyme, Cellevolve Bio, Inc., Seagen Inc. and ICON (Teva). He has carried out legal consulting for Lewis, Thomason, King, Krieg and Waldrop (PML) and Loughren, Loughren, Loughren Powell Gilbert LLP. He serves on the Data Safety Monitoring Board for Wave Life Sciences, Excision Biotherapeutics Inc, Sanofi, Genzyme, Atara Biotherapeutics Inc, Cellevolve Bio, Inc. G.W. serves as a consultant for Alector and Pharmapace. He serves on the data safety monitoring board for Eli Lilly and Co.

AD reports no competing interests.

CS reports no competing interests.

RJB is Director of DIAN–TU and Principal Investigator of DIAN–TU‐001. He receives research support from the NIA of the NIH, DIAN–TU trial pharmaceutical partner (Hoffman‐La Roche Ltd), Alzheimer's Association, GHR Foundation, Anonymous Organization, DIAN–TU Pharma Consortium (Active: AbbVie, Biogen, BMS, Eisai, Eli Lilly & Co., Ionis, Janssen, Prothena, Roche/Genentech. Previous: Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi, United Neuroscience). He has been a scientific advisor for NAPA Advisory Council Biogen, F. Hoffman‐La Roche/Genentech Ltd, UK Dementia Research Institute at University College London and Stanford University. He has been an invited speaker for Alzheimer's Association, Duke Margolis Alzheimer's Roundtable, BrightFocus Foundation, Tau Consortium, NAPA Advisory Council on Alzheimer's Research, CTAD, FBRI, Beeson, Adler Symposium and Fondazione Prada. R.J.B. is a co‐founders of C2N Diagnostics and receive income from C2N Diagnostics for serving on the scientific advisory board. Washington University has equity ownership interest in C2N Diagnostics. R.J.B. is a co‐inventors of the stable isotope labeling kinetics and blood plasma assay technology licensed by Washington University to C2N Diagnostics. Through these relationships, Washington University, R.J.B. is entitled to receive royalties and/or equity from the license agreement with C2N. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Soluble tau biomarkers track disease progression in Dominantly inherited Alzheimer disease natural history cohort. (A) mean cross‐sectional standardized values (y‐axis) for soluble tau‐related biomarkers (in CentiMarkers), clinical dementia rating sum of boxes (CDR‐SB) and amyloid PET for MCs across the estimated year of onset (EYO) (x‐axis). (B) percentage (y‐axis) of MCs with abnormal levels (greater than 2 SD above mean of NC) of soluble tau‐related biomarkers, CDR‐SB and amyloid PET across the EYO (x‐axis) in 5‐year intervals.
FIGURE 2
FIGURE 2
Gantenerumab and solanezumab treatment has distinct effects on amyloid PET and tau biomarkers. Estimated mean change in CentiMarkers from baseline with 95% confidence intervals for the treatment (gantenerumab (blue), solanezumab (red)) and shared placebo groups using MMRM analyses. (A, B) Estimated mean change from baseline in amyloid (PiB) PET and Tau‐PET for gantenerumab. (C, D) Estimated mean change from baseline in %phospho‐tau153. (E, F) Estimated mean change from baseline in %phospho‐tau181. (G, H) Estimated mean change from baseline in %phospho‐tau205. (I, J) Estimated mean change from baseline in %phospho‐tau217. (K, L) Estimated mean change from baseline in %phospho‐tau231. (M, N) Estimated mean change from baseline in MTBR‐tau243. (O, P) Estimated mean change from baseline in total tau (Lumipulse immunoassay). Sample sizes at yearly assessments are listed below the x axes. Each drug group was compared to the shared placebo group independently using the MMRM model. *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 3
FIGURE 3
Change in CSF tau biomarkers and PET measures of tau and amyloid‐beta show distinct relationships. Correlation (ρ) between the estimate annual rate of change in amyloid PiB‐PET (blue) or tau PET (green) and in each tau biomarker. %phospho‐tau153 and amyloid PiB‐PET (ρ = 0.37, CI [0.15, 0.56] p = 0.001) and tau PET (ρ = ‐0.08, CI [‐ 0.31, 0.16] p = 0.52); %phospho‐tau181 and amyloid PiB‐PET (ρ = 0.45, CI [0.24, 0.62] p < 0.0001) and tau PET (ρ = ‐0.40, CI [‐0.58, ‐0.19] p < 0.001); %phospho‐tau205 and amyloid PiB‐PET (ρ = 0.14, CI [‐0.10, 0.36] p = 0.25) and tau PET (ρ = 0.22, CI [‐0.02, 0.43] p = 0.07); %phospho‐tau217 and amyloid PiB‐PET (ρ = 0.50, CI [0.30, 0.66] p < 0.0001) and tau PET (ρ = ‐0.17, CI [‐0.39, 0.06] p < 0.15); %phospho‐tau231 and amyloid PiB‐PET (ρ = 0.35, CI [0.13, 0.54] p = 0.0027) and tau PET (ρ = ‐0.25, CI [‐0.46, ‐0.02] p = 0.03); MTBR‐tau243 and amyloid PiB‐PET (ρ = 0.15, CI [‐0.09, 0.38] p = 0.2018) and tau PET (ρ = 0.47, CI [0.28, 0.64] p < 0.001); total tau and amyloid PiB‐PET (ρ = 0.23, CI [‐0.02, 0.45] p = 0.06) and tau PET (ρ = 0.1, CI [0.‐15, 0.33] p = 0.44).
FIGURE 4
FIGURE 4
Gantenerumab effects on the biomarker trajectories of DIAD. Purple hashed‐dot represents mutation carrier placebo‐control; blue hashed represents mutation carrier gantenerumab treated group; green solid line represents non‐carrier placebo‐control. EYO‐ estimated years to onset of symptoms; (A) PiB‐PET (standard uptake value ratio (SUVR)); (B) Tau‐PET (SUVR), (C) hippocampal volume (based on MRI) mm3; (D) %phospho‐tau153; (E) %phospho‐tau181; (F) %phospho‐tau205; (G) %phospho‐tau217; (H); (G) %phospho‐tau23; (I) Microtuble binding region (MTBR)‐ tau243; (J) total tau level.
See this image and copyright information in PMC

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