A model of brain function to predict tau across Alzheimer’s disease and related disorders

We developed a machine learning framework grounded in a computational model of brain function and FDG-PET imaging to predict Alzheimer’s disease (AD)-type tau across AD and related disorders (ADRD). The model was trained on 1088 research participants spanning normal aging and ADRD with FDG-PET and flortaucipir-PET (FTP-PET). Validation was conducted in: (1) a longitudinal subset of the training cohort (n = 215), (2) Alzheimer’s Disease Neuroimaging Initiative (n = 295), and (3) a heretogeneous clinical cohort (n = 264; n = 28 with FTP-PET).

Results showed that the model accurately predicted FTP-PET when applied at the participant-level (R2 ~ 0.34-0.71). It performed well in clinical scenarios, including classification of low versus high tau stages (79–95% accuracy) and prediction of tau in a heterogeneous clinical cohort without FTP-PET. These findings advance the understanding of the relationship between neurodegeneration and AD-type tau and provide a framework for estimating AD-type tau across ADRD.

We wish to express our gratitude towards our patients and their caregivers’ dedication to our research programs as well as to healthcare providers involved in their clinical care. This work was funded in part by National Institutes of Health (NIH) grants (P30 AG062677 to D.J.), (U01 AG082350-01A1 to D.J.), (R37 AG011378 to C.J.), (R01 AG041851 to C.J.), (P50 AG016574 to R.P.), (U01 AG006786 to R.P.), (R01-AG50603, R01-DC12519, R01-DC14942, R37-NS89757, R21-NS94684 to JLW and KAJ) and by the Robert Wood Johnson Foundation, The Elsie and Marvin Dekelboum Family Foundation, The Liston Family Foundation, the Edson Family, The GHR Foundation, Foundation Dr Corinne Schuler (Geneva, Switzerland). NCL is funded by a 2026 NARSAD Young Investigator Grant from the Brain and Behavior Foundation.

JL is funded by Research fund of Hanyang University (HY-202400000003953) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2026-25487883). Data collection and sharing for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is funded by the National Institute on Aging (National Institutes of Health Grant U19AG024904). The grantee organization is the Northern California Institute for Research and Education.

In the past, ADNI has also received funding from the National Institute of Biomedical Imaging and Bioengineering, the Canadian Institutes of Health Research, and private sector contributions through the Foundation for the National Institutes of Health (FNIH) including generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; BristolMyers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. A full list of members and their affiliations appears in the Supplementary Information.

Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA Nick Corriveau-Lecavalier, Gemeng Zhang, Hugo Botha, Leland R. Barnard, Venkatsampath R. Gogineni, Jonathan Graff-Radford, Vijay K.