Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease
Authors: Erickson Pontus , Simrén Joel , Brum Wagner S. , Ennis Gilda E. , Kollmorgen Gwendlyn , Suridjan Ivonne , Langhough Rebecca , Jonaitis Erin M. , Van Hulle Carol A. , Betthauser Tobey J. , Carlsson Cynthia M. , Asthana Sanjay , Ashton Nicholas J. , Johnson Sterling C. , Shaw Leslie M. , Blennow Kaj , Andreasson Ulf , Bendlin Barbara B. , Zetterberg Henrik ,   ADNI Cohort, Weiner Michael , 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 , Shaw Leslie M. , Liu Enchi , Montine Tom , Thomas Ronald G. , Donohue Michael , Walter Sarah , Gessert Devon , Sather Tamie , Jiminez Gus , Harvey Danielle , Bernstein Matthew , Fox Nick , Thompson Paul , Schuff Norbert , DeCArli Charles , Borowski Bret , Gunter Jeff , Senjem Matt , Vemuri Prashanthi , Jones David , Kantarci Kejal , Ward Chad , Koeppe Robert A. , Foster Norm , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Cairns Nigel J. , Householder Erin , Taylor Reinwald Lisa , Lee Virginia , Korecka Magdalena , Figurski Michal , Crawford Karen , Neu Scott , Foroud Tatiana M. , Potkin Steven , Shen Li , Kelley Faber , Kim Sungeun , Nho Kwangsik , Kachaturian Zaven , Frank Richard , J Snyder Peter J. , Molchan Susan , Kaye Jeffrey , Quinn Joseph , Lind Betty , Carter Raina , Dolen Sara , Schneider Lon S. , Pawluczyk Sonia , Beccera Mauricio , Teodoro Liberty , M Spann Bryan M. , Brewer James , Vanderswag Helen , Fleisher Adam , Heidebrink Judith L , Lord Joanne L , Mason Sara , Albers Colleen , Knopman David , Johnson Kris , Doody Rachelle S , Villanueva Meyer Javier , Chowdhury Munir , Rountree Susan , Dang Mimi , Stern Yaakov , Honig Lawrence S , Bell Karen L , Ances Beau , Morris John C , Carroll Maria , Leon Sue , Mintun Mark A , Schneider Stacy , OliverNG Angela , Griffith Randall , Clark David , Geldmacher David , Brockington John , Roberson Erik , Grossman Hillel , Mitsis Effie , deToledo-Morrell Leyla , Shah Raj C , Duara Ranjan , Varon Daniel , Greig Maria T , Roberts Peggy , Albert Marilyn , Onyike Chiadi , D’Agostino Daniel , Kielb Stephanie , Galvin James E , Pogorelec Dana M , Cerbone Brittany , Michel Christina A , Rusinek Henry , de Leon Mony J , Glodzik Lidia , De Santi Susan , Murali Doraiswamy P , R Petrella Jeffrey , Z Wong Terence , E Arnold Steven , H Karlawish Jason , Wolk David , D Smith Charles , Jicha Greg , Hardy Peter , Sinha Partha , Oates Elizabeth , Conrad Gary , Lopez Oscar , Oakley MaryAnn , Simpson Donna , Porsteinsson Anton , Goldstein Bonnie , Martin Kim , Makino Kelly , Saleem Ismail M , Brand Connie , Mulnard Ruth , Thai Gaby , Mc Adams Ortiz Catherine , Womack Kyle , Mathews Dana , Quiceno Mary , Diaz Arrastia Ramon , King Richard , Weiner Myron , Martin Cook Kristen , DeVous Michael , Levey Allan , Lah James , Cellar Janet , Burns Jeffrey , Anderson Heather , Swerdlow Russell , Apostolova Liana , Tingus Kathleen , Woo Ellen , Silverman Daniel , Lu Po , Bartzokis George , Graff Radford Neill , ParfittH Francine , Kendall Tracy , Johnson Heather , Farlow Martin , Marie Hake Ann , Matthews Brandy , Herring Scott , Hunt Cynthia , van Dyck Christopher , Carson Richard , MacAvoy Martha G , Chertkow Howard , Bergman Howard , Hosein Chris , Black Sandra , Stefanovic Bojana , Caldwell Curtis , Yuek Robin Hsiung Ging , Feldman Howard , Mudge Benita , Assaly Past Michele , Kertesz Andrew , Rogers John , Trost Dick , Bernick Charles , Munic Donna , Kerwin Diana , Marsel Mesulam Marek , Lipowski Kristine , Kuo Wu Chuang , Johnson Nancy , Sadowsky Carl , Martinez Walter , Villena Teresa , Scott Turner Raymond , Johnson Kathleen , Reynolds Brigid , Sperling Reisa A , Johnson Keith A , Marshall Gad , Frey Meghan , Yesavage Jerome , Taylor Joy L , Lane Barton , Rosen Allyson , Tinklenberg Jared , Sabbagh Marwan N , Belden Christine M , Jacobson Sandra A , Sirrel Sherye A , Kowall Neil , Killiany Ronald , Budson Andrew E , Norbash Alexander , Lynn Johnson Patricia , Obisesan Thomas O , Wolday Saba , Allard Joanne , Lerner Alan , Ogrocki Paula , Hudson Leon , Fletcher Evan , Carmichael Owen , Olichney John , DeCarli Charles , Kittur Smita , Borrie Michael , Lee T Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M , G Potkin Steven G , Preda Adrian , Nguyen Dana , Tariot Pierre , Reeder Stephanie , Bates Vernice , Capote Horacio , Rainka Michelle , Scharre Douglas W , Kataki Maria , Adeli Anahita , Zimmerman Earl A , Celmins Dzintra , Brown Alice D , Pearlson Godfrey D , Blank Karen , Anderson Karen , Santulli Robert B , Kitzmiller Tamar J , Schwartz Eben S , SinkS Kaycee M , Williamson Jeff D , Garg Pradeep , Watkins Franklin , Ott Brian R , Querfurth Henry , Tremont Geoffrey , Salloway Stephen , Malloy Paul , Correia Stephen , Rosen Howard J , Miller Bruce L , Mintzer Jacobo , Spicer Kenneth , Bachman David , Finger Elizabether , Pasternak Stephen , Rachinsky Irina , Drost Dick , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Schultz Susan K , Boles Ponto Laura L , Shim Hyungsub , Elizabeth Smith Karen , Relkin Norman , Chaing Gloria , Raudin Lisa , Smith Amanda , Fargher Kristin , Ashok Raj Balebail 
Published: July 2023

Importance

Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid–negative, tau-positive (A−T+) cerebrospinal fluid (CSF) biomarker profile.

Objective

To estimate the prevalence of a CSF A−T+ biomarker profile and investigate its clinical implications.

Design, Setting, and Participants

This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023.

Exposures

Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240).

Main Outcomes and Measures

Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A−T+ vs A−T− groups. Secondary outcomes included cross-sectional tau-PET.

Results

A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A−T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A−T+ and A−T− profiles for cognition or imaging biomarkers. Cross-sectionally, A−T+ had similar tau-PET uptake to individuals with an A−T− biomarker profile.

Conclusion and Relevance

Results suggest that the CSF A−T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.