Clinical performance of plasma P‐tau217 for the identification of primary Alzheimer’s disease pathology or co‐pathology in sporadic frontotemporal dementia

Abstract Background As 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. Method Participants 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. Result Plasma 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. Conclusion Even 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.

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Journal
Alzheimer s & Dementia
Published
2024-12-01
DOI
https://doi.org/10.1002/alz.089822
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
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article

Clinical performance of plasma P‐tau217 for the identification of primary Alzheimer’s disease pathology or co‐pathology in sporadic frontotemporal dementia

Nicholas K. Proctor, Lawren VandeVrede, Sandra Weıntraub, Julio C. Rojas et al.
Alzheimer s & Dementia
Dementia and Cognitive Impairment Research
article

Clinical performance of plasma P‐tau217 for the identification of primary Alzheimer’s disease pathology or co‐pathology in sporadic frontotemporal dementia

Nicholas K. Proctor, Lawren VandeVrede, Sandra Weıntraub, Julio C. Rojas, Jonathan Graff‐Radford, Irene Litvan, Hilary W. Heuer, Dennis W. Dickson, Adam M. Staffaroni, Arthur W. Toga, Maria Carmela Tartaglia, Daniel H. Geschwind, Adam L. Boxer, Zbigniew K. Wszołek, Anne M. Fagan, Peter Alexander Ljubenkov, Belén Pascual, John Kornak, Kimiko Domoto‐Reilly, Joseph C. Masdeu, Ian Grant, Bonnie Wong, Maria I. Lapid, Katya Rascovsky, Jill Goldman, Otto Pedraza, Eric J. Huang, Corey T. McMillan, Jeffrey L. Dage, Julie A. Fields, Bruce L. Miller, Brad C. Dickerson, Chiadi U. Onyike, Hugo Botha, Murray Grossman, Tatiana Foroud, Rosa Rademakers, Toji Miyagawa, Ian R. Mackenzie, Gianina Toller, Walter K. Kremers, Leonard Petrucelli, David S. Knopman, Elisabeth H. Thijssen, Ging‐Yuek Robin Hsiung, Giovanni Coppola, David Thomas Jones, Jessica E. Rexach, Bradley F. Boeve, Danielle Brushaber, Howard J. Rosen, Igor Araújo, Douglas R Galasko, Jamie Fong, Leah K. Forsberg, Kejal Kantarci, Edward D. Huey, Brian S. Appleby, Mario F. Mendez, David J. Irwin, Binita Rajbanshi, Erik D. Roberson, Katherine P. Rankin, Ralitza H. Gavrilova, Nupur Ghoshal, Yvette Bordelon, Aaron Ritter, Neill R. Graff‐Radford, Gabriel C. Léger, Eliana Marisa Ramos, Diane Lucente, Argentina Lario Lago, William W. Seeley
article en

Abstract

Abstract Background As 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. Method Participants 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. Result Plasma 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. Conclusion Even 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.

Alzheimer s & DementiaVol. 20(S2)
Northwestern University (US), University of Southern California (US), Houston Methodist (US), Cleveland Clinic (US), Mayo Clinic (US), Harvard University (US), University of British Columbia (CA), Johns Hopkins University (US), University of Antwerp (BE), University of California, Los Angeles (US), Eli Lilly (United States) (US), University of California, San Francisco (US), University of Toronto (CA), University of Washington (US), Washington University in St. Louis (US), Johns Hopkins Medicine (US), Kantonsspital St. Gallen (CH), Lou Ruvo Brain Institute (US), WinnMed (US), University of Alabama at Birmingham (US), University of California San Diego (US), Massachusetts General Hospital (US), University Memory and Aging Center (US), Alzheimer’s Disease Neuroimaging Initiative (US), Mayo Clinic in Arizona (US), VIB-UAntwerp Center for Molecular Neurology (BE), Mayo Clinic in Florida (US), Amsterdam University Medical Centers (NL), Case Western Reserve University (US), The University of Tokyo (JP), Columbia University (US), University of Pennsylvania (US), Vrije Universiteit Amsterdam (NL)
Openalex Percentile: Top 65%
Dementia and Cognitive Impairment Research
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