Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Authors: Hu William T. , Ozturk Tugba , Kollhoff Alexander , Wharton Whitney , Christina Howell J. ,   Alzheimer’s Disease Neuroimaging Initiative, 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 , Perrin Richard J. , Shaw Leslie M. , Kachaturian Zaven , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , González Hector , Ho Carole , Hsiao John K. , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Ryan Laurie , Silverberg Nina , Fleisher Adam , Montine Tom , Kaye Jeffrey A. , Silbert Lisa C. , Schneider Lon S. , Pawluczyk Sonia , Becerra Mauricio , Brewer James , Heidebrink Judith L. , Knopman David , Villanueva-Meyer Javier , Doody Rachelle S. , Kass Joseph S. , Stern Yaakov , Honig Lawrence S. , Mintz Akiva , Ances Beau , Mintun Mark A. , Geldmacher David , Love Marissa Natelson , Grossman Hillel , Goldstein Martin A. , Shah Raj C. , Lamar Melissa , Duara Ranjan , Greig-Custo Maria T. , Albert Marilyn , Onyike Chiadi , Smith Amanda , Sadowski Martin , Wisniewski Thomas , Shulman Melanie , Doraiswamy P. Murali , Petrella Jeffrey R. , James Olga , Karlawish Jason H. , Wolk David A. , Smith Charles D. , Jicha Gregory A. , El Khouli Riham , Lopez Oscar L. , Porsteinsson Anton P. , Thai Gaby , Pierce Aimee , Kelley Brendan , Nguyen Trung , Womack Kyle , Levey Allan I. , Lah James J. , Burns Jeffrey M. , Swerdlow Russell H. , Brooks William M. , Silverman Daniel H. S. , Kremen Sarah , Graff-Radford Neill R. , Farlow Martin R. , van Dyck Christopher H. , Mecca Adam P. , Chertkow Howard , Vaitekunis Susan , Black Sandra , Stefanovic Bojana , Heyn Chinthaka , Hsiung Ging-Yuek Robin , Sossi Vesna , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Grant Ian , Rogalski Emily , Mesulam M.-Marsel , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J. , Miller Bruce L. , Perry David , Turner Raymond Scott , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A. , Yesavage Jerome , Taylor Joy L. , Chao Steven , Belden Christine M. , Atri Alireza , Spann Bryan M. , Killiany Ronald , Stern Robert , Mez Jesse , Obisesan Thomas O. , Ntekim Oyonumo E. , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fletcher Evan , Maillard Pauline , Olichney John , DeCarli Charles , Bates Vernice , Capote Horacio , Borrie Michael , Lee T.-Y. , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Perrin Allison , Scharre Douglas W. , Kataki Maria , Tarawneh Rawan , Hart David , Zimmerman Earl A. , Celmins Dzintra , Miller Delwyn D. , Koleva Hristina , Shim Hyungsub , Williamson Jeff D. , Craft Suzanne , Cleveland Jo , Ott Brian R. , Drake Jonathan , Tremont Geoffrey , Sabbagh Marwan , Ritter Aaron , Mintzer Jacobo , Masdeu Joseph , Shi Jiong , Newhouse Paul , Potkin Steven , Salloway Stephen , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D. , Blank Karen , Flashman Laura A. , Seltzer Marc , Lee Athena , Relkin Norman , Chiang Gloria 
Published: June 2021

Neuroinflammation is associated with Alzheimer’s disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer’s Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer’s disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer’s disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer’s markers.