Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology
Taylor W. Schmitz(MRC Cognition and Brain Sciences Unit), R. Nathan Spreng(Cornell University), The Alzheimer's Disease Neuroimaging Initiative(University of California, San Francisco), Michael W. Weiner(University of California, San Francisco), Paul Aisen(Mayo Clinic), Ronald C. Petersen(Mayo Clinic), Clifford R. Jack(Mayo Clinic), William J. Jagust(University of Pennsylvania), 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 C. Morris(Washington University in St. Louis), Leslie M. Shaw(University of California San Diego), Zaven S. Khachaturian(Siemens (Germany)), Greg Sorensen(Siemens (Germany)), Lew Kuller(University of Pittsburgh), Marc Raichle(Washington University in St. Louis), Steven M. Paul(Albert Einstein College of Medicine), Peter Davies(Albert Einstein College of Medicine), Howard Fillit(Alzheimer's Drug Discovery Foundation), Franz Hefti(Washington University in St. Louis), Davie Holtzman(Northwestern University), M. Marcel Mesulam(Northwestern University), William Z. Potter(Brown University), Peter J. Snyder(Eli Lilly (United States)), Adam J. Schwartz(Eli Lilly (United States)), Tom Montine(University of Washington), Ronald G. Thomas(University of California San Diego), Michael Donohue(University of California San Diego), Sarah Walter(University of California San Diego), Devon Gessert(University of California San Diego), Tamie Sather(University of California San Diego), Gus Jiminez(University of California San Diego), Danielle Harvey(Mayo Clinic), Matt A. Bernstein(University of London), Nick C. Fox(University of London), Paul M. Thompson(University of California, San Francisco), Norbert Schuff(Mayo Clinic), Bret Borowski(Mayo Clinic), Jeff Gunter(Mayo Clinic), Matthew L. Senjem(Mayo Clinic), Prashanthi Vemuri(Mayo Clinic), David T. Jones(Mayo Clinic), Kejal Kantarci(Mayo Clinic), Chad Ward(Mayo Clinic), Robert A. Koeppe(University of Utah), Norm Foster(Alzheimer's Association), Eric M. Reiman(Alzheimer's Association), Kewei Chen(Alzheimer's Association), Chet Mathis(University of Pittsburgh), Susan Landau(Washington University in St. Louis), Nigel J. Cairns(Washington University in St. Louis), Erin Householder(Washington University in St. Louis), Lisa Taylor‐Reinwald(Washington University in St. Louis), Virginia 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 Michigan), Steven Potkin(University of Michigan), Li Shen(Indiana University Bloomington), Kelley Faber(Indiana University Bloomington), Sungeun Kim(Indiana University Bloomington), Kwangsik Nho(University of California San Diego), Leon J. Thal(University of California San Diego), Neil Buckholtz(Johns Hopkins University), Marylyn Albert(Johns Hopkins University), Richard Frank(National Institute on Aging), John Hsiao(Oregon Health & Science University), 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(LAC+USC Medical Center), Lon S. Schneider(LAC+USC Medical Center), Sonia Pawluczyk(LAC+USC Medical Center), Mauricio Beccera(LAC+USC Medical Center), Liberty Teodoro(LAC+USC Medical Center), Bryan M. Spann(LAC+USC Medical Center), James Brewer(University of California San Diego), Helen Vanderswag(Alzheimer's Association), Adam Fleisher(Alzheimer's Association), Judith L. Heidebrink(University of Michigan), Joanne Lord(Mayo Clinic), Sara S. Mason(Mayo Clinic), Colleen S. Albers(Mayo Clinic), David S. Knopman(Mayo Clinic), 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(Baylor College of Medicine), Lawrence S. Honig(Baylor College of Medicine), Karen L. Bell(Baylor College of Medicine), Beau M. Ances(Washington University in St. Louis), Maria Carroll(Washington University in St. Louis), Sue Leon(Washington University in St. Louis), Mark A. Mintun(Washington University in St. Louis), Stacy Schneider(Washington University in St. Louis), Angela Oliver(Washington University in St. Louis), Daniel Marson(University of Alabama at Birmingham), Randall Griffith(University of Alabama at Birmingham), David 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 U. Onyike(Johns Hopkins University), Daniel D’Agostino(Johns Hopkins University), Stephanie Kielb(Johns Hopkins University), James E. Galvin(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 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(Johns Hopkins University), Donna M. Simpson(Johns Hopkins University), 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 Rochester Medical Center), Ruth A. Mulnard(UC Irvine Health), Gaby Thai(UC Irvine Health), Catherine Mc-Adams-Ortiz(UC Irvine Health), 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 Kansas Medical Center), Liana G. Apostolova, Kathleen Tingus, Ellen Woo, Daniel Silverman, Po H. Lu, George Bartzokis(WinnMed), Neill R. Graff‐Radford(WinnMed), Francine Parfitt(WinnMed), Tracy Kendall(WinnMed), Heather Johnson(WinnMed), Martin R. Farlow(Indiana University Bloomington), AnnMarie 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(Jewish General Hospital), Howard Chertkow(Jewish General Hospital), Howard Bergman(Jewish General Hospital), 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(University of British Columbia), Howard Feldman(University of British Columbia), Benita Mudge(University of British Columbia), Michele Assaly(Cleveland Clinic), Andrew Kertesz(Cleveland Clinic), John Rogers(St Joseph's Health Care), Charles Bernick(St Joseph's Health Care), Donna Munic(Northwestern University), Diana Kerwin(Northwestern University), Marek-Marsel Mesulam(Northwestern University), Kristine Lipowski(Northwestern University), Chuang‐Kuo Wu(Northwestern University), Nancy 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 A. Marshall(Brigham and Women's Hospital), Meghan Frey(Brigham and Women's Hospital), Barton Lane(Brigham and Women's Hospital), Allyson Rosen(Brigham and Women's Hospital), Jared Tinklenberg(Brigham and Women's Hospital), 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(Boston University), Neil W. Kowall(Boston University), Ronald Killiany(Boston University), Andrew E. Budson(Boston University), Alexander Norbash(Boston University), Patricia Lynn Johnson(Boston 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(Parkwood Institute), Michael Borrie(Parkwood Institute), T.-Y. Lee(Parkwood Institute), 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 G. Potkin(University of Michigan), Adrian Preda(University of Michigan), Dana Nguyen(Alzheimer's Association), Pierre N. Tariot(Alzheimer's Association), Stephanie Reeder(Alzheimer's Association), 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. Sink(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 Care), 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(University of California, San Francisco), Thomas C. Neylan(Northwestern University), Jordan Grafman(Northwestern University), Melissa Davis(University of California San Diego), Rosemary Morrison(University of California, San Francisco), Jacqueline Hayes(University of California, San Francisco), Shannon Finley(United States Department of Defense), Karl E. Friedl(Rush University Medical Center), Debra Fleischman(Rush University Medical Center), Konstantinos Arfanakis(Rush University Medical Center), Olga James(Medical University of South Carolina), Dino Massoglia(University of Wisconsin–Madison), J. Jay Fruehling(University of Wisconsin–Madison), Sandra Harding(University of Wisconsin–Madison), Elaine R. Peskind(University of Washington), Eric C. Petrie(The Ohio State University), Gail Li(The Ohio State University), Jerome A. Yesavage(Stanford University), Joy L. Taylor(Stanford University), Ansgar J. Furst(Stanford University)
Cited by 347Open Access
Abstract
There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
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