Clinical performance of plasma P‐tau217 for the identification of primary Alzheimer’s disease pathology or co‐pathology in sporadic frontotemporal dementia
Authors: Araujo Igor Prufer Q C , Rojas Julio C. , VandeVrede Lawren , Ljubenkov Peter A. , Heuer Hilary W. , Miller Bruce L. , Seeley William W. , Staffaroni Adam M. , Rajbanshi Binita , Lago Argentina Lario , Thijssen Elisabeth H , Toller Gianina , Proctor Nicholas , Forsberg Leah K. , Forsberg Leah K. , Brushaber Danielle , Ramos Eliana Marisa , Coppola Giovanni , Appleby Brian , Bordelon Yvette M. , Botha Hugo , Dickerson Brad C , Dickson Dennis W. , Domoto‐Reilly Kimiko , Fagan Anne M. , Fields Julie A. , Fong Jamie C , Foroud Tatiana M. , Galasko Douglas R. , Gavrilova Ralitza H. , Geschwind Daniel H. , Goldman Jill S , Ghoshal Nupur , Graff‐Radford Neill R , Graff‐Radford Jonathan , Grant Ian , Grossman Murray , Hsiung Ging‐Yuek Robin , Huang Eric J. , Huey Edward D. , Irwin David J , Jones David T. , Knopman David S. , Kornak John , Kantarci Kejal , Kremers Walter K. , Lapid Maria I. , Leger Gabriel C , Litvan Irene , Lucente Diane E. , MacKenzie Ian R , Masdeu Joseph C. , McMillan Corey T , Mendez Mario F. , Miyagawa Toji , Onyike Chiadi U. , Pascual Belen , Pedraza Otto , Petrucelli Leonard , Rademakers Rosa , Rankin Katherine P. , Rascovsky Katya , Rexach Jessica E , Ritter Aaron , Roberson Erik D , Tartaglia Maria Carmela , Toga Arthur W. , Weintraub Sandra , Wong Bonnie , Wszolek Zbigniew , Dage Jeffrey L. , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. 
Published: January 2025

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.