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. 2025 Apr;21(4):e14423.
doi: 10.1002/alz.14423.

Characterizing visual read tau-PET-negative participants with Alzheimer's disease dementia

Roos M Rikken  1   2   3 , Emma M Coomans  3   4 , Lotte A de Koning  1   2   3 , Denise Visser  1   2 , Eline Neutelings  1 , Anouk den Braber  3   4   5 , Lyduine E Collij  1   2   6 , Sandeep S V Golla  1   2 ; Alzheimer's Disease Neuroimaging Initiative; Frederik Barkhof  1   2   7 , Pieter Jelle Visser  3   4   8   9 , Philip Scheltens  3   4 , Wiesje M van der Flier  3   4   10 , Ronald Boellaard  1   2 , Rik Ossenkoppele  3   4   6 , Everard G B Vijverberg  3   4 , Elsmarieke van de Giessen  1   2 ; for ADNI
Affiliations

Characterizing visual read tau-PET-negative participants with Alzheimer's disease dementia

Roos M Rikken et al. Alzheimers Dement. 2025 Apr.

Abstract

Introduction: A subset of amyloid beta (Aβ)-positive Alzheimer's disease (AD) patients is tau-positron emission tomography (PET) negative. We aimed to characterize this subgroup using [18F]flortaucipir PET visual read (VR), as this is important for prognosis and selection for therapies.

Methods: Aβ-positive VR tau-PET-negative AD dementia patients (AD A+T-) were compared to tau-PET-positive AD patients (AD A+T+) and control groups (CU A-T-; CU A+T-) included from the Amsterdam-based cohort and Alzheimer's Disease Neuroimaging Initiative (ADNI). We compared [18F]flortaucipir binding in an early- and late-stage tau ROI, atrophy, cognition, and co-pathologies.

Results: AD A+T- were older, showed less hippocampal atrophy and slower cognitive decline compared to AD A+T+. In ADNI, AD A+T- showed higher early-stage tau binding compared to both control groups and more late-stage tau compared to CU A-T-, but no tau accumulation over time.

Discussion: VR tau-PET-negative AD patients show neurodegenerative and cognitive processes consistent with the AD trajectory, but milder progression compared to tau-PET-positive AD patients.

Highlights: We used the novel Food and Drug Administration (FDA)-approved VR method for defining tau-PET positivity. AD A+T- patients were older and showed less atrophy and cognitive decline than AD A+T+. We did not find convincing evidence of tau accumulation in AD A+T- or copathologies. The group of AD A+T- patients is likely very heterogeneous.

Keywords: Alzheimer's disease dementia; tau‐PET; visual read; [18F]flortaucipir.

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Conflict of interest statement

A.B. has received research funding/support from Alzheimer Nederland, Alzheimer Association, Weston Brain Institute, Selfridges Group Foundation, Stichting Dioraphte, and Health Holland. All funding has been paid to the institutions. L.E.C. has acquired research support from GE Healthcare and Springer Healthcare (paid by Eli Lilly), both paid to the institution. L.E.C.'s salary is supported by the MSCA Postdoctoral fellowship (101108819) and Alzheimer Association Research Fellowship (23AARF‐1029663) grants. Research programs of W.M.F. were funded by ZonMW, NWO, EU‐JPND, EU‐IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, Stichting Dioraphte, Gieskes‐Strijbis fonds, Stichting Equilibrio, Edwin Bouw fonds, Pasman Stichting, Stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc., Novartis‐NL, Life‐MI, AVID, Roche BV, Fujifilm, Eisai, and Combinostics. W.M.F. holds the Pasman chair. W.M.F. is the recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). W.M.F. is the recipient of TAP‐dementia (www.tap‐dementia.nl), receiving funding from ZonMw (10510032120003). TAP‐dementia receives co‐financing from Avid Radiopharmaceuticals and Amprion. All funding is paid to her institution. W.M.F. has been an invited speaker at Biogen MA Inc., Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, and European Brain Council. W.M.F. is a consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc., and Eisai. W.M.F. participated in advisory boards of Biogen MA Inc., Roche, and Eli Lilly. W.M.F. is a member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. W.M.F. is a member of the steering committee of PAVE and Think Brain Health. W.M.F. was associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M.F. is associate editor at Brain. R.O. has received research funding/support from European Research Council, ZonMw, NWO, National Institutes of Health, Alzheimer's Association, Alzheimer Nederland, Stichting Dioraphte, Cure Alzheimer's fund, Health Holland, ERA PerMed, Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics, has given lectures in symposia sponsored by GE Healthcare, is an advisory board member for Asceneuron, and a steering committee member for Bristol Myers Squibb. All the aforementioned have been paid to the institutions. R.O. is an editorial board member of Alzheimer's Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. E.G. has received research support from NWO, ZonMw, Hersenstichting, Alzheimer Nederland, Health∼Holland, and KWF. E.G. has performed contract research for Heuron Inc. and Roche. E.G. has a consultancy agreement with IXICO and Life Molecular Imaging for reading of PET scans. P.S. is an employee of EQT Life Sciences (formerly LSP). E.G.B.V. is the PI for DIAN trials, WashU, ACI, Alnylam, CogRX Therapeutics, New Amsterdam Pharma, Janssen, Roche, Vivoryon, ImmunoBrain, Alector, Biogen, BMS, Prothena, GSK, Aviadobio, Treeway. E.G.B.V. is consultant for New Amsterdam Pharma, Treeway, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Roche, Eli Lilly en Esai. E.G.B.V. has received research support from NWO, ZonMw, Hersenstichting, and Health∼Holland. F.B. is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, Eisai, and Prothena, an advisory board member for Combinostics, and Scottish Brain Sciences, and a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, Bracco. He has research agreements with ADDI, Merck, Biogen, GE Healthcare, and Roche and is co‐founder and shareholder of Queen Square Analytics LTD. R.M.R., E.M.C., L.A.K., D.V., E.N., S.S.V.G., P.J.V. and R.B. have no disclosures. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Baseline and longitudinal [18F]flortaucipir binding in early‐ and late‐stage tau ROIs. (A–D) Boxplots showing baseline [18F]flortaucipir binding in early‐ (MTL) and late‐stage tau ROIs per group. (E–H) Plots showing [18F]flortaucipir binding in early‐ and late‐stage tau ROIs per group over time. The reported p values are derived from the baseline values of an age‐ and sex‐adjusted linear mixed model. Longitudinal tau‐PET data available in Amsterdam: AD A+T− 3/10; AD A+T+ 27/75; CU A−T− 31/92; CU A+T− 14/39. Logitudinal tau‐PET data available in ADNI: AD A+T−12/18; AD A+T+ 23/58; CU A−T− 114/268; CU A+T− 71/112. MTL, medial temporal lobe; PET, positron emission tomography; ROI, region of interest. * p < 0.05.
FIGURE 2
FIGURE 2
Longitudinal cognition. (A, B) Plot showing composite memory domain z‐scores over time in the Amsterdam‐based cohort and ADNI. (C) Plot showing composite non‐memory domain z‐scores over time in the Amsterdam‐based cohort. (D) Plot showing composite executive functioning domain z‐scores over time in ADNI. (E) Plot showing composite language domain z‐scores over time in ADNI. Time is relative to baseline [18F]flortaucipir PET, a positive value meaning after [18F]flortaucipir PET and a negative value meaning before [18F]flortaucipir PET. ADNI, Alzheimer's Disease Neuroimaging Initiative; PET, positron emission tomography.
FIGURE 3
FIGURE 3
Hippocampal volume and cortical thickness. (A) Boxplot showing residuals of hippocampal volume corrected for intracranial volume in the Amsterdam‐based cohort. (B) Boxplot showing residuals of hippocampal volume corrected for intracranial volume in ADNI. (C) Boxplot showing global cortical thickness in millimeters in the Amsterdam‐based cohort. (D) Boxplot showing global cortical thickness in millimeters in ADNI. Missing ADNI: AD A+T− 6/18 global cortical thickness, 4/17 hippocampal volume; AD A+T+ hippocampal volume 19/58, global cortical thickness 18/58; CU A−T− global cortical thickness 62/268, hippocampal volume 67/268; CU A+T− hippocampal volume 23/112, global cortical thickness 24/112. Missing Amsterdam: AD A+T− global cortical thickness 0/10, hippocampal volume 0/10; AD A+T+ global cortical thickness 3/75 hippocampal volume 3/75; CU A−T− global cortical thickness, 7/92 hippocampal volume 4/92; CU A+T− global cortical thickness 2/39, hippocampal volume 2/39. ADNI, Alzheimer's Disease Neuroimaging Initiative. * p < 0.05.
FIGURE 4
FIGURE 4
Visualizing the heterogeneity in co‐pathologies in AD A+T− and AD A+T+. (A) Pie chart showing co‐pathologies in AD A+T− in Amsterdam‐based cohort. (B) Pie chart showing co‐pathologies in AD A+T− in ADNI. (C) Pie chart showing co‐pathologies in AD A+T+ in Amsterdam‐based cohort. (D) Pie chart showing co‐pathologies in AD A+T+ in ADNI. WMH‐positivity based on >1.5 SD with reference to subset of <65‐year CU A−T−. Alpha‐synuclein status was only available in ADNI. Missing values are reported as negative. In the Amsterdam‐based cohort, WMH status was missing for one subject (10%) in AD A+T− and two subjects (4.55%) in AD A+T+. In ADNI the missing values in AD A+T− were 1 (5.56%) WMH status, 4 (22.22%) V status, and alpha‐synuclein status was missing in six subjects (33.33%). In ADNI the missing values in AD A+T+ were 13 (22.41%) for V, 1 (1.72%) for WMH, and alpha‐synuclein status was missing in 14 (24.14%) subjects. ADNI, Alzheimer's Disease Neuroimaging Initiative; Asyn, alpha‐synuclein; V, vascular/infarct status; WMH, white matter hyperintensities.
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