Tau topography subtypes account for clinical heterogeneity and longitudinal trajectories in early-onset Alzheimer's disease

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ID: 314114
2026
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Abstract
Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left Temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modeling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared to the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.
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Authors Marlene Lin, Konstantinos Chiotis, Piyush Maiti, J. Zhang, Ganna Blazhenets, Salma Rocha, Ranjani Shankar, Alinda Amuiri, Dustin Hammers, Ani Eloyan, Kala Kirby, Robert A Koeppe, Paul Aisen, Laurel Beckett, Walter A Kukull, Arthur W Toga, Alireza Atri, David Clark, Gregory S Day, Ranjan Duara, Neill R Graff-Radford, Ian Grant, Lawrence S Honig, Erik C B Johnson, David T Jones, Joseph C Masdeu, Mario F Mendez, Erik Musiek, Chiadi U Onyike, Meghan Riddle, Emily Rogalski, Stephen Salloway, Sharon J Sha, Raymond Scott Turner, Thomas S Wingo, David A Wolk, Kyle B Womack, Kelly Nudelman, Alexandra Touroutoglou, Clifford R Jack, Prashanthi Vemuri, Jacob W Vogel, Suzanne M. Dufault, Thomas J Hoffmann, Maria C Carrillo, Bradford C Dickerson, Liana G Apostolova, Gil D Rabinovici, Renaud La Joie
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag176
URL
https://doi.org/10.1093/braincomms/fcag176
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