Diagnostic value of plasma P‐tau217 in frontotemporal dementia spectrum disorders
Authors: Rojas Julio C. , Vandevrede Lawren , Heuer Hilary W. , Toller Gianina , Thijssen Elisabeth H. , Proctor Nicholas , 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 Doug R. , Gavrilova Ralitza H. , Geschwind Daniel H. , Ghoshal Nupur , Goldman Jill , 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. , Kantarci Kejal , Knopman David S. , Kornak John , Kremers Walter K. , Lapid Maria I. , Leger Gabriel C. , Litvan Irene , Ljubenkov Peter A. , Lucente Diane E. , Mackenzie Ian R. , Masdeu Joseph C. , McMillan Corey T. , Mendez Mario , Miller Bruce L. , 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. , Savica Rodolfo , Seeley William W. , Staffaroni Adam M. , Trataglia Maria Carmela , Toga Arthur W. , Weintraub Sandra , Wong Bonnie , Wszolek Zbigniew , Dage Jeffrey L. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. 
Published: February 2022

Background

Frontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.

Method

Plasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.

Result

The sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.

Conclusion

When FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.