Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
Jacob W. Vogel(Montreal Neurological Institute and Hospital), Yasser Iturria‐Medina(Montreal Neurological Institute and Hospital), Olof Strandberg(Lund University), Ruben Smith(Lund University), Elizabeth Levitis(Montreal Neurological Institute and Hospital), Alan C. Evans(Montreal Neurological Institute and Hospital), Oskar Hansson(Lund University), Alzheimer’s Disease Neuroimaging Initiative(University of California, San Francisco), Michael W. Weiner(University of California, San Francisco), Paul Aisen(UC San Diego Health System), Ronald Petersen(Mayo Clinic in Florida), Clifford R. Jack(Berkeley College), William J. Jagust(Berkeley College), John Q. Trojanowki(LAC+USC Medical Center), Arthur W. Toga(LAC+USC Medical Center), Laurel Beckett(Brigham and Women's Hospital), Robert C. Green(Brigham and Women's Hospital), Andrew J. Saykin(Washington University in St. Louis), John R. Morris(Washington University in St. Louis), Leslie M. Shaw(Janssen (United States)), Enchi Liu(University of Washington), Tom Montine(University of Washington), Ronald G. Thomas(UC San Diego Health System), Michael Donohue(UC San Diego Health System), Sarah Walter(UC San Diego Health System), Devon Gessert(UC San Diego Health System), Tamie Sather(UC San Diego Health System), Gus Jiminez(UC San Diego Health System), Danielle Harvey(UC San Diego Health System), Michael Donohue(UC San Diego Health System), Matt A. Bernstein(University of London), Nick C. Fox(University of London), Paul M. Thompson(LAC+USC Medical Center), Norbert Schuff(University of California, Davis), Charles DeCarli(Mayo Clinic in Florida), Bret Borowski(Mayo Clinic in Florida), Jeff Gunter(Mayo Clinic in Florida), Matthew L. Senjem(Mayo Clinic in Florida), Prashanthi Vemuri(Mayo Clinic in Florida), David T. Jones(Mayo Clinic in Florida), Kejal Kantarci(Mayo Clinic in Florida), Chad Ward(University of Michigan), Robert A. Koeppe(University of Utah), Norm Foster(University of Utah), Eric M. Reiman(Banner Alzheimer’s Institute), Kewei Chen(University of Pittsburgh), Chet Mathis(Berkeley College), Susan Landau(Berkeley College), Nigel J. Cairns(Washington University in St. Louis), Erin Householder(Washington University in St. Louis), Lisa Taylor Reinwald(Washington University in St. Louis), Virginia M.‐Y. Lee(University of Pennsylvania), Magdalena Korecka(University of Pennsylvania), Michal Figurski(LAC+USC Medical Center), Karen Crawford(LAC+USC Medical Center), Scott Neu(LAC+USC Medical Center), Tatiana Foroud(University of California, Irvine), Steven G. Potkin(University of California, Irvine), Li Shen(Indiana University Bloomington), Kelley Faber(Indiana University Bloomington), Sungeun Kim(Indiana University Bloomington), Kwangsik Nho(Alzheimer's Association), Zaven Kachaturian(Alzheimer's Association), Richard Frank(General Electric (United States)), Peter J. Snyder(National Institutes of Health), Susan Molchan(National Institutes of Health), Jeffrey Kaye(Oregon Health & Science University), Joseph F. Quinn(Oregon Health & Science University), Betty Lind(Oregon Health & Science University), Raina Carter(Oregon Health & Science University), Sara Dolen(University of Southern California), Lon S. Schneider(University of Southern California), Sonia Pawluczyk(University of Southern California), Mauricio Beccera(University of Southern California), Liberty Teodoro(University of Southern California), Bryan M. Spann(University of Southern California), James M. Brewer(University of California San Diego), Helen Vanderswag(University of California San Diego), Adam Fleisher(University of Michigan), Judith L. Heidebrink(University of Michigan), Joanne Lord(University of Michigan), Ronald Petersen(Mayo Clinic in Florida), Sara S. Mason(Mayo Clinic in Florida), Colleen S. Albers(Mayo Clinic in Florida), David S. Knopman(Mayo Clinic in Florida), Kris Johnson(Brigham and Women's Hospital), Rachelle S. Doody(Baylor College of Medicine), Javier Villanueva Meyer(Baylor College of Medicine), Munir Chowdhury(Baylor College of Medicine), Susan Rountree(Baylor College of Medicine), Mimi Dang(Baylor College of Medicine), Yaakov Stern(Columbia University Irving Medical Center), Lawrence S. Honig(Columbia University Irving Medical Center), Karen L. Bell(Washington University in St. Louis), Beau M. Ances(Washington University in St. Louis), John C. Morris(Washington University in St. Louis), Maria Carroll(Washington University in St. Louis), Sue Leon(Washington University in St. Louis), Erin Householder(Washington University in St. Louis), Mark A. Mintun(Washington University in St. Louis), Stacy Schneider(Washington University in St. Louis), Angela OliverNG(University of Alabama at Birmingham), Randall Griffith(University of Alabama at Birmingham), David W. Clark(University of Alabama at Birmingham), David Geldmacher(University of Alabama at Birmingham), John Brockington(University of Alabama at Birmingham), Erik D. Roberson(University of Alabama at Birmingham), Hillel Grossman(Icahn School of Medicine at Mount Sinai), Effie Mitsis(Rush University Medical Center), Leyla de Toledo‐Morrell(Rush University Medical Center), Raj C. Shah(Rush University Medical Center), Ranjan Duara, Daniel Varón, Maria T. Greig, Peggy Roberts(Johns Hopkins University), Marilyn Albert(Johns Hopkins University), Chiadi Onyike(Johns Hopkins University), Daniel D’Agostino(Johns Hopkins University), Stephanie Kielb(Johns Hopkins University), James E. Galvin(New York University), Dana M. Pogorelec(New York University), Brittany Cerbone(New York University), Christina A. Michel(New York University), Henry Rusinek(New York University), Mony J. de Leon(New York University), Lidia Glodzik(New York University), Susan De Santi(Duke Medical Center), P. Murali Doraiswamy(Duke Medical Center), Jeffrey R. Petrella(Duke Medical Center), Terence Z. Wong(Duke Medical Center), Steven E. Arnold(University of Pennsylvania), Jason H. Karlawish(University of Pennsylvania), David A. Wolk(University of Kentucky), Charles D. Smith(University of Kentucky), Gregory A. Jicha(University of Kentucky), Peter Hardy(University of Kentucky), Partha Sinha(University of Kentucky), Elizabeth Oates(University of Kentucky), Gary Conrad(University of Kentucky), Oscar L. López(University of Pittsburgh), MaryAnn Oakley(University of Pittsburgh), Donna M. Simpson(University of Pittsburgh), Anton P. Porsteinsson(University of Rochester Medical Center), Bonnie S. Goldstein(University of Rochester Medical Center), Kim Martin(University of Rochester Medical Center), Kelly M. Makino(University of Rochester Medical Center), M. Saleem Ismail(University of Rochester Medical Center), Connie Brand(University of California, Irvine), Ruth A. Mulnard(University of California, Irvine), Gaby Thai(University of California, Irvine), Catherine Mc Adams Ortiz(University of California, Irvine), Kyle Womack(The University of Texas Southwestern Medical Center), Dana Mathews(The University of Texas Southwestern Medical Center), Mary Quiceno(The University of Texas Southwestern Medical Center), Ramon Diaz Arrastia(The University of Texas Southwestern Medical Center), Richard King(The University of Texas Southwestern Medical Center), Myron Weiner(University of California, San Francisco), Kristen Martin Cook(The University of Texas Southwestern Medical Center), Michael D. Devous(Emory University), Allan I. Levey(Emory University), James J. Lah(Emory University), Janet S. Cellar(Emory University), Jeffrey M. Burns(University of Kansas Medical Center), Heather S. Anderson(University of Kansas Medical Center), Russell H. Swerdlow(University of California, Los Angeles), Liana Apostolova(University of California, Los Angeles), Kathleen Tingus(University of California, Los Angeles), Ellen Woo(University of California, Los Angeles), Daniel Silverman(University of California, Los Angeles), Po H. Lu(University of California, Los Angeles), George Bartzokis(University of California, Los Angeles), Neill R. Graff Radford(WinnMed), Francine Parfitt(WinnMed), Tracy Kendall(WinnMed), Heather Johnson(WinnMed), Martin R. Farlow(Indiana University Bloomington), Ann Marie Hake(Indiana University Bloomington), Brandy R. Matthews(Indiana University Bloomington), Scott Herring(Indiana University Bloomington), Cynthia Hunt(Yale University), Christopher H. van Dyck(Yale University), Richard E. Carson(Yale University), Martha G. MacAvoy(Yale University), Howard Chertkow, Howard Bergman, Chris Hosein(Sunnybrook Health Science Centre), Sandra E. Black(Sunnybrook Health Science Centre), Bojana Stefanovic(Sunnybrook Health Science Centre), Curtis Caldwell(Sunnybrook Health Science Centre), Ging‐Yuek Robin Hsiung, Howard Feldman, Benita Mudge, Michele Assaly Past(St Joseph's Health Centre), Andrew Kertesz(St Joseph's Health Centre), John Rogers(St Joseph's Health Centre), Dick Trost(Cleveland Clinic), Charles Bernick(Cleveland Clinic), Donna Munic(Northwestern University), Diana Kerwin(Northwestern University), Marek Marsel Mesulam(Northwestern University), Kristine Lipowski(Northwestern University), Chuang Wu(Northwestern University), Nancy E. Johnson(Northwestern University), Carl Sadowsky(Palm Beach Neurology), Walter Martínez(Palm Beach Neurology), Teresa Villena(Georgetown University), Raymond Scott Turner(Georgetown University), Kathleen Johnson(Brigham and Women's Hospital), Brigid Reynolds(Brigham and Women's Hospital), Reisa A. Sperling(Brigham and Women's Hospital), Keith A. Johnson(Brigham and Women's Hospital), Gad Marshall(Brigham and Women's Hospital), Meghan Frey(Brigham and Women's Hospital), Jerome A. Yesavage(Stanford University), Joy L. Taylor(Stanford University), Barton Lane(Stanford University), Allyson Rosen(Stanford University), Jared Tinklenberg(Banner Sun Health Research Institute), Marwan N. Sabbagh(Banner Sun Health Research Institute), Christine M. Belden(Banner Sun Health Research Institute), Sandra A. Jacobson(Banner Sun Health Research Institute), Sherye A. Sirrel(Banner Sun Health Research Institute), Neil W. Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson(Howard University), Thomas O. Obisesan(Howard University), Saba Wolday(Howard University), Joanne Allard(Howard University), Alan J. Lerner(Case Western Reserve University), Paula Ogrocki(Case Western Reserve University), Leon Hudson(Case Western Reserve University), Evan Fletcher(University of California, Davis), Owen Carmichael(University of California, Davis), John Olichney(University of California, Davis), Charles DeCarli(University of California, Davis), Smita Kittur(Beaumont Hospital, Dearborn), Michael Borrie(Beaumont Hospital, Dearborn), T. Y. Lee(Beaumont Hospital, Dearborn), Robert Bartha(University of Wisconsin–Madison), Sterling C. Johnson(University of Wisconsin–Madison), Sanjay Asthana(University of Wisconsin–Madison), Cynthia M. Carlsson(University of Wisconsin–Madison), Steven Potkin(University of California, Irvine), Adrian Preda(University of California, Irvine), Dana Nguyen(University of California, Irvine), Pierre N. Tariot(Banner Alzheimer’s Institute), Adam Fleisher(Banner Alzheimer’s Institute), Stephanie Reeder(Dent Neurologic Institute), Vernice Bates(Dent Neurologic Institute), Horacio Capote(Dent Neurologic Institute), Michelle Rainka(Dent Neurologic Institute), Douglas W. Scharre(The Ohio State University), Maria Kataki(The Ohio State University), Anahita Adeli(The Ohio State University), Earl A. Zimmerman(Albany Medical Center Hospital), Dzintra Celmins(Albany Medical Center Hospital), Alice D. Brown(Hartford Hospital), Godfrey D. Pearlson(Hartford Hospital), Karen Blank(Hartford Hospital), Karen Anderson(Dartmouth–Hitchcock Medical Center), Robert B. Santulli(Dartmouth–Hitchcock Medical Center), Tamar J. Kitzmiller(Dartmouth–Hitchcock Medical Center), Eben S. Schwartz(Dartmouth–Hitchcock Medical Center), Kaycee M. SinkS(Wake Forest University), Jeff D. Williamson(Wake Forest University), Pradeep Garg(Wake Forest University), Franklin Watkins(Rhode Island Hospital), Brian R. Ott(Rhode Island Hospital), Henry Querfurth(Rhode Island Hospital), Geoffrey Tremont(Providence College), Stephen Salloway(Providence College), Paul Malloy(Providence College), Stephen Correia(University of California, San Francisco), Howard J. Rosen(University of California, San Francisco), Bruce L. Miller(Medical University of South Carolina), Jacobo Mintzer(Medical University of South Carolina), Kenneth Spicer(Medical University of South Carolina), David Bachman(Medical University of South Carolina), Elizabeth Finger(St Joseph's Health Care), Stephen Pasternak(St Joseph's Health Care), Irina Rachinsky(St Joseph's Health Centre), John Rogers(St Joseph's Health Centre), Andrew Kertesz(St Joseph's Health Centre), Dick Drost(Nathan Kline Institute for Psychiatric Research), Nunzio Pomara(Nathan Kline Institute for Psychiatric Research), Raymundo Hernando(Nathan Kline Institute for Psychiatric Research), Antero Sarrael(Nathan Kline Institute for Psychiatric Research), Susan K. Schultz(University of Iowa), Laura L. Boles Ponto(University of Iowa), Hyungsub Shim(University of Iowa), Karen E. Smith(University of Iowa), Norman Relkin(Cornell University), Gloria Chaing(Cornell University), Lisa Raudin(Cornell University), Amanda Smith(University of South Florida), Kristin Fargher(University of South Florida), Balebail Ashok Raj(Lund University), the Swedish BioFinder Study(Lund University), Emelie Andersson(Lund University), David Berron(Lund University), Elin Byman(Lund University), Tone Sundberg-Brorsson(Lund University), Administrator(Lund University), Emma Borland(Lund University), Anna Callmer(Lund University), Cecilia Dahl(Lund University), Eske Christiane Gertje(Lund University), Anna‐Märta Gustavsson(Lund University), Joanna Grzegorska(Lund University), Sara Hall(Lund University), Oskar Hansson(Lund University), Philip S. Insel(Lund University), Shorena Janelidze(Lund University), Maurits Johansson(Lund University), Helena Sletten(Lund University), Jonas Jester-Broms(Lund University), Elisabet Londos(Lund University), N. S. Mattson(Lund University), Lennart Minthon(Lund University), Maria H Nilsson(Lund University), Rosita Nordkvist(Lund University), Katarina Nägga(Lund University), Camilla Orbjörn(Lund University), Rik Ossenkoppele(Lund University), Sebastian Palmqvist(Lund University), Marie Persson(Lund University), Alexander Santillo(Lund University), Nicola Spotorno(Lund University), Erik Stomrud(Lund University), Håkan Toresson(Lund University), Olof Strandberg(Lund University), Michael Schöll(Lund University), Ida M. Friberg, Per Johansson(Skåne University Hospital), Moa Wibom(Skåne University Hospital), Katarina Johansson(Skåne University Hospital), Emma Pettersson(Skåne University Hospital), Christin Karremo(Skåne University Hospital), Ruben Smith(Lund University), Yulia Surova(Lund University), Mattis Jalakas(Lund University), Jimmy Lätt(Lund University), Peter Mannfolk(Lund University), Markus Nilsson(Lund University), Freddy Ståhlberg(Lund University), Pia C. Sundgren(Lund University), Danielle van Westen(Lund University), Ulf Andréasson(University of Gothenburg), Kaj Blennow(Karolinska Institutet), Henrik Zetterberg(Karolinska Institutet), Lars‐Olof Wahlund(Karolinska Institutet), Eric Westman(Lund University), Joana B. Pereira(Lund University), Jonas Jögi(Lund University), Douglas Hägerström(Lund University), Tomas Olsson(Lund University), Per Wollmer(Lund University)
Cited by 536Open Access
Abstract
Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aβ is present, but regions with greater Aβ burden show greater tau than predicted by connectivity patterns, suggesting a role of Aβ in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aβ.
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