Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status
Authors: Shen Xue-Ning , Huang Yu-Yuan , Chen Shi-Dong , Guo Yu , Tan Lan , Dong Qiang , Yu Jin-Tai ,   Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W. , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John C. , Perrin Richard J. , Shaw Leslie M. , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , González Hector , Ho Carole , Hsiao John K. , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Perrin Richard , Ryan Laurie , Silverberg Nina , Fleisher Adam , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Miriam , Flenniken Derek , Kormos Adrienne , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Cabrera Yuliana , Walter Sarah , Miller Garrett , Coker Godfrey , Clanton Taylor , Hergesheimer Lindsey , Smith Stephanie , Adegoke Olusegun , Mahboubi Payam , Moore Shelley , Pizzola Jeremy , Shaffer Elizabeth , Sloan Brittany , Harvey Danielle , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjem Matthew , Vemuri Prashanthi , Reid Robert , Fox Nick C. , Malone Ian , Thompson Paul , Thomopoulos Sophia I. , Nir Talia M. , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Tosun-Turgut Duygu , Chen Stephanie Rossi , Choe Mark , Crawford Karen , Yushkevich Paul A. , Das Sandhitsu , Koeppe Robert A. , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Perrin Richard , Cairns Nigel J. , Householder Erin , Franklin Erin , Bernhardt Haley , Taylor-Reinwald Lisa , Shaw Leslie M. , Trojanowki John Q. , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Saykin Andrew J. , Nho Kwangsik , Risacher Shannon L. , Apostolova Liana G. , Shen Li , Foroud Tatiana M. , Nudelman Kelly , Faber Kelley , Wilmes Kristi , Thal Leon , Khachaturian Zaven , Hsiao John K. , Silbert Lisa C. , Lind Betty , Crissey Rachel , Kaye Jeffrey A. , Carter Raina , Dolen Sara , Quinn Joseph , Schneider Lon S. , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M. , Brewer James , Vanderswag Helen , Fleisher Adam , Ziolkowski Jaimie , Heidebrink Judith L. , Zbizek-Nulph Lisa , Lord Joanne L. , Albers Colleen S. , Knopman David , Johnson Kris , Villanueva-Meyer Javier , Pavlik Valory , Pacini Nathaniel , Lamb Ashley , Kass Joseph S. , Doody Rachelle S. , Shibley Victoria , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S. , Mintz Akiva , Ances Beau , Winkfield David , Carroll Maria , Stobbs-Cucchi Georgia , Oliver Angela , Creech Mary L. , Mintun Mark A. , Schneider Stacy , Geldmacher David , Love Marissa Natelson , Griffith Randall , Clark David , Brockington John , Marson Daniel , Grossman Hillel , Goldstein Martin A. , Greenberg Jonathan , Mitsis Effie , Shah Raj C. , Lamar Melissa , Samuels Patricia , Duara Ranjan , Greig-Custo Maria T. , Rodriguez Rosemarie , Albert Marilyn , Onyike Chiadi , Farrington Leonie , Rudow Scott , Brichko Rottislav , Kielb Stephanie , Smith Amanda , Raj Balebail Ashok , Fargher Kristin , Sadowski Martin , Wisniewski Thomas , Shulman Melanie , Faustin Arline , Rao Julia , Castro Karen M. , Ulysse Anaztasia , Chen Shannon , Sheikh Mohammed O. , Singleton-Garvin Jamika , Doraiswamy P. Murali , Petrella Jeffrey R. , James Olga , Wong Terence Z. , Borges-Neto Salvador , Karlawish Jason H. , Wolk David A. , Vaishnavi Sanjeev , Clark Christopher M. , Arnold Steven E. , Smith Charles D. , Jicha Gregory A. , El Khouli Riham , Raslau Flavius D. , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Martin Kim , Kowalski Nancy , Keltz Melanie , Goldstein Bonnie S. , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Quiceno Mary , Levey Allan I. , Lah James J. , Hajjar Ihab , Cellar Janet S. , Burns Jeffrey M. , Swerdlow Russell H. , Brooks William M. , Silverman Daniel H. S. , Kremen Sarah , Apostolova Liana , Tingus Kathleen , Lu Po H. , Bartzokis George , Woo Ellen , Teng Edmond , Graff-Radford Neill R. , Parfitt Francine , Poki-Walker Kim , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Brosch Jared R. , Herring Scott , van Dyck Christopher H. , Mecca Adam P. , Good Susan P. , MacAvoy Martha G. , Carson Richard E. , Varma Pradeep , Chertkow Howard , Vaitekunis Susan , Hosein Chris , Black Sandra , Stefanovic Bojana , Heyn Chris , Hsiung Ging-Yuek Robin , Kim Ellen , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Rogers John , Grant Ian , Muse Brittanie , Rogalski Emily , Robson Jordan , Mesulam M.-Marsel , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J. , Miller Bruce L. , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A. , Belden Christine M. , Atri Alireza , Spann Bryan M. , Clark Kelly A. , Zamrini Edward , Sabbagh Marwan , Killiany Ronald , Stern Robert , Mez Jesse , Kowall Neil , Budson Andrew E. , Obisesan Thomas O. , Ntekim Oyonumo E. , Wolday Saba , Khan Javed I. , Nwulia Evaristus , Nadarajah Sheeba , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Carmichael Owen , Bates Vernice , Capote Horacio , Rainka Michelle , Borrie Michael , Lee T-Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Perrin Allison , Burke Anna , Scharre Douglas W. , Kataki Maria , Tarawneh Rawan , Kelley Brendan , Hart David , Zimmerman Earl A. , Celmins Dzintra , Miller Delwyn D. , Boles Ponto Laura L. , Smith Karen Ekstam , Koleva Hristina , Shim Hyungsub , Nam Ki Won , Schultz Susan K. , Williamson Jeff D. , Craft Suzanne , Cleveland Jo , Yang Mia , Sink Kaycee M. , Ott Brian R. , Drake Jonathan , Tremont Geoffrey , Daiello Lori A. , Drake Jonathan D. , Sabbagh Marwan , Ritter Aaron , Bernick Charles , Munic Donna , Mintz Akiva , O’Connelll Abigail , Mintzer Jacobo , Wiliams Arthur , Masdeu Joseph , Shi Jiong , Garcia Angelica , Sabbagh Marwan , Newhouse Paul , Potkin Steven , Salloway Stephen , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D. , Blank Karen , Anderson Karen , Flashman Laura A. , Seltzer Marc , Hynes Mary L. , Santulli Robert B. , Relkin Norman , Chiang Gloria , Lin Michael , Ravdin Lisa , Lee Athena , Petersen Ron , Neylan Thomas , Grafman Jordan , Montine Tom , Danowski Sarah , Nguyen-Barrera Catherine , Finley Shannon , Harvey Danielle , Donohue Michael , Bernstein Matthew , Foster Norm , Foroud Tatiana M. , Potkin Steven , Shen Li , Faber Kelley , Kim Sungeun , Nho Kwangsik , Wilmes Kristi , Vanderswag Helen , Fleisher Adam , Sood Ajay , Blanchard Kimberly S. , Fleischman Debra , Greig Maria T. , Goldstein Bonnie , Martin Kimberly S. , Thai Gaby , Pierce Aimee , Reist Christopher , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Sadowsky Carl , Martinez Walter , Villena Teresa , Rosen Howard , Peskind Elaine R. , Petrie Eric C. , Li Gail , Yesavage Jerome , Taylor Joy L. , Chao Steven , Coleman Jaila , White Jessica D. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Jimenez-Maggiora Gustavo , Drake Erin , Donohue Mike , Nelson Craig , Bickford David , Butters Meryl , Zmuda Michelle , Borowski Bret , Gunter Jeff , Senjem Matt , Kantarci Kejal , Ward Chad , Reyes Denise , Faber Kelley M. , Nudelman Kelly N. , Au Yiu Ho , Scherer Kelly , Catalinotto Daniel , Stark Samuel , Ong Elise , Fernandez Dariella , Zmuda Michelle 
Published: November 2021

Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ = 0.45, P < 0.0001), tau (0.25, P = 0.0003), and FDG PET uptakes (−0.37, P < 0.0001), and increased along the Alzheimer’s continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level (>18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology.