Abstract
Purpose
The aim of this study was to compare regional brain tau extent across the disease spectrum in early- and late-onset Alzheimer’s disease using the second-generation tau PET tracer [18F]RO948, and to investigate the relationship between PET-derived patterns, plasma p-tau217, brain atrophy, and cognition.
Methods
We examined 57 participants: 39 patients from the Cognitive Assessment Unit at Karolinska University Hospital (Stockholm/Sweden)—diagnosed as MCI Aβ– (n = 10), MCI Aβ + (n = 16; 8 EO and 6 LO), and AD (n = 13; 5 EOAD and 8 LOAD)—and 18 cognitively normal controls. All participants underwent [18F]RO948 tau-PET, structural MRI, cognitive testing, and plasma p-tau217 analysis.
Results
Both EO and LO MCI (Aß +) showed higher [18F]RO948 binding in amygdala, entorhinal cortex, hippocampus (p < 0.001) and extending to inferior temporal regions (p < 0.01) compared to controls, with some MCI-EO cases already showing advanced neocortical tau burden. At the AD stage, EOAD patients showed greater neocortical tau extent in temporo-parietal and frontal cortices than LOAD. P‑tau217 positively correlated with [18F]RO948 in amygdala, entorhinal cortex, hippocampus (rho = 0.81) followed by temporal (rho = 0.71), and parietal cortices (rho = 0.56, all p < 0.001). The Tau‑PET/p-tau217 association was different between EOAD and LOAD with greater differences in parietal cortices. Tau‑PET also showed stronger region‑specific associations with cognitive impairment than p‑tau217, especially in EOAD.
Conclusions
[18F]RO948-PET captured interindividual heterogeneity in tau accumulation that was not reflected by plasma p-tau217. This dissociation was particularly evident in neocortical regions, where LOAD showed elevated plasma p-tau217 levels despite low tau PET binding. These findings highlight the value of tau-PET as a sensitive biomarker for detecting early disease heterogeneity, assessing disease severity, and improving patient stratification for disease-modifying treatments.
Authors and Affiliations
Mariola Zapater-Fajari¹, Marco Bucci¹˒², Konstantinos Chiotis¹˒³, Ove Almkvist¹˒³, Anders Wall⁴˒⁵, Jonas Eriksson⁵˒⁶, Gunnar Antoni⁵˒⁶, Ilaria Pola⁷, Kübra Tan⁷, Wiebke Traichel⁷˒⁸, Andrea L. Benedet⁷, Nicholas J. Ashton⁷˒⁹˒¹⁰, Henrik Zetterberg⁷˒¹¹˒¹²˒¹³˒¹⁴˒¹⁵˒¹⁶, Nenad Bogdanovic¹˒³, and Agneta Nordberg¹˒³*
¹ Department of Neurobiology, Care Sciences and Society, Centre for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Neo 7th Floor, Stockholm 14183, Sweden
² Turku PET Center, Turku University Central Hospital, University of Turku and Åbo Akademi University, Turku 20251, Finland
³ Theme Inflammation and Aging, Karolinska University Hospital, Stockholm 14186, Sweden
⁴ Department of Surgical Sciences, Section of Molecular Imaging & Medical Physics, Uppsala University, Uppsala 75185, Sweden
⁵ PET Centre, Uppsala University Hospital, Uppsala 75185, Sweden
⁶ Department of Medicinal Chemistry, Uppsala University, Uppsala 75123, Sweden
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden
⁸ Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Frederik V’s Vej 11, 3, Copenhagen 2100, Denmark
⁹ Institute of Psychiatry, Psychology & Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RT, UK
¹⁰ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London SE5 8AF, UK
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 43180, Sweden
¹² Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
¹³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong 999077, China
¹⁴ Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison 53792-2420, USA
¹⁵ Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison 53792-2420, USA
¹⁶ Centre for Brain Research, Indian Institute of Science, C.V. Raman Avenue, Bangalore 560 012, India
* Corresponding author