Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology.

Taylor W Schmitz,Balebail Ashok Raj,Sue Leon,Eben S Schwartz,Gus Jiminez,Angela Oliver,Bruce L Miller,Magdalena Korecka,Greg Jicha,Kewei Chen,Ruth A Mulnard,Anahita Adeli,Danielle Harvey,John Rogers,Owen Carmichael,Tamar J Kitzmiller,Kathleen Tingus,Robert B Santulli,Susan De Santi,Ronald Killiany,Gail Li,Nunzio Pomara,Kristin Fargher,Jeff Gunter,Randall Griffith,Susan K Schultz,John Olichney,Jerome A Yesavage,Norbert Schuff,Michael Borrie,Donna M Simpson,Cynthia Hunt,Robert C Green,Gloria Chaing,Arthur W Toga,James E Galvin,Franklin Watkins,Francine Parfitt,Henry Rusinek,Yaakov Stern,Susan Landau,Christine M Belden,Kenneth Spicer,Godfrey D Pearlson,Daniel D’Agostino,Steven G Potkin,Ging-Yuek Robin Hsiung,Sonia Pawluczyk,Matt Senjem,Marilyn Albert,T.-Y Lee,Teresa Villena,M Saleem Ismail,Curtis Caldwell,Sherye A Sirrel,Evan Fletcher,Meghan Frey,Melissa Davis,Howard Feldman,Leslie M Shaw,Olga James,Geoffrey Tremont,Andrew E Budson,Heather Johnson,Howard J Rosen,Jeffrey R Petrella,Martin R Farlow,Sandra Harding,Jeff D Williamson,Brandy R Matthews,Rob Bartha,Kwangsik Nho,Stephanie Reeder,Sungeun Kim,Greg Sorensen,Devon Gessert,Jeffrey M Burns,Michael W Weiner,Antero Sarrael,Charles Bernick,Ellen Woo,Rachelle S Doody,Gary Conrad,Gaby Thai,Nigel J Cairns,Lawrence S Honig,Jordan Grafman,Mary Quiceno,Peter Davies,Sara Dolen,Stephen Correia,Partha Sinha,Smita Kittur,Maria T Greig,Michal Figurski,Carl Sadowsky,Howard Fillit,Elaine R Peskind,Scott Herring,Davie Holtzman,James J Lah,Eric M Reiman,Alexander Norbash,Virginia Lee,Charles D Smith,Kyle Womack,Alice D Brown,Karen L Bell,Terence Z Wong,Colleen S Albers,Lidia Glodzik,Brittany Cerbone,Leon Hudson,Marylyn Albert,Michelle Rainka,Karen Crawford,Ranjan Duara,Effie Mitsis,P Murali Doraiswamy,Marc Raichle,Munir Chowdhury,Clifford R Jack,Benita Mudge,Earl A Zimmerman,Janet S Cellar,Elizabeth Oates,Kristine Lipowski,Laura L Boles Ponto,Chris Hosein,Henry Querfurth,Po H Lu,Barton Lane,Connie Brand,Allyson Rosen,Stephanie Kielb,Bryan M Spann,Jacobo Mintzer,Brian R Ott,Annmarie Hake,Jacqueline Hayes,Lew Kuller,Stephen Salloway,Andrew J Saykin,Bonnie S Goldstein,Kelley Faber,Franz Hefti,Russell H Swerdlow,Nancy Johnson,Paul Malloy,Debra Fleischman,Sanjay Asthana,Catherine Mc-Adams-Ortiz,Helen Vanderswag,J Jay Fruehling,Chad Ward,Li Shen,Steven E Arnold,Peter Hardy,Michele Assaly,Tracy Kendall,David Bachman,Chet Mathis,Douglas W Scharre,Liberty Teodoro,Norman Relkin,Prashanthi Vemuri,Martha G Macavoy,Joy L Taylor,Stephen Pasternak,Peggy Roberts,Lisa Raudin,Bret Borowski,R Nathan Spreng,Lon S Schneider,Karen Anderson,Jeffrey Kaye,Dana Nguyen,Horacio Capote,Christopher H Van Dyck,Kelly M Makino,Michael Donohue,Howard Chertkow,Amanda Smith,Christina A Michel,Richard King,Vernice Bates,Ansgar J Furst,Joanne Allard,Paula Ogrocki,Maryann Oakley,Tamie Sather,Erin Householder,John Brockington,Stacy Schneider,Mauricio Beccera,Myron Weiner,Marwan N Sabbagh,Kris Johnson,Tom Montine,Heather S Anderson,Kaycee M Sink,Howard Bergman,Cynthia M Carlsson,Marek-Marsel Mesulam,Elizabether Finger,Karen Blank,Mimi Dang,Kathleen Johnson,Raymond Scott Turner,Brigid Reynolds,Raina Carter,Anton P Porsteinsson,Sarah Walter,Irina Rachinsky,Kristen Martin-Cook,Maria Kataki,Mark A Mintun,Keith A Johnson,Susan Rountree,Charles Decarli,Donna Munic,Diana Kerwin,Sandra A Jacobson,Scott Neu,Dino Massoglia,Judith L Heidebrink,Norm Foster,Andrew Kertesz,Reisa A Sperling,Adam Fleisher,Richard E Carson,Kejal Kantarci,Sara S Mason,Dzintra Celmins,Konstantinos Arfanakis,Maria Carroll,Hillel Grossman,Shannon Finley,Betty Lind,Raj C Shah,Pradeep Garg,Rosemary Morrison,Dana Mathews,Ronald G Thomas,John Q Trojanowki,George Bartzokis,Hyungsub Shim,Eric C Petrie,Robert A Koeppe,Adrian Preda,Kim Martin,Mony J De Leon,Raymundo Hernando,William Z Potter ,Thomas C Neylan ,David S Geldmacher ,James B Brewer ,Alan J Lerner ,Chiadi U Onyike ,Neil S Buckholtz ,Laurel A Beckett ,Zaven S Khachaturian ,Ramon Diaz‐Arrastia ,David S Knopman ,Oscar L López ,John C Morris ,Richard A Frank ,Neil W Kowall ,Jason Karlawish ,David T Jones ,Daniel Varón ,Beau M Ances ,Michael D Devous ,Leon J Thal ,Nick C Fox ,Leyla De Toledo‐Morrell ,Aĺlan I Levey ,Lisa Taylor‐Reinwald ,Daniel C Marson ,Liana G Apostolova ,Patricia Johnson ,Adam J Schwartz ,Bojana Stefanović ,Jared R Tinklenberg ,Karen E Smith ,Peter J Snyder ,Tatiana Foroud ,John K Hsiao ,Paul M Thompson ,Sandra E Black ,Javier Villanueva‐Meyer ,Ronald C Petersen ,David A Wolk ,Karl E Friedl ,Gad A Marshall ,Steven M Paul ,Pierre N Tariot ,Erik D Roberson ,Chuang‐Kuo Wu ,Neill R Graff‐Radford ,Sterling C Johnson ,William J Jagust ,Daniel Silverman ,Matt A Bernstein ,Marsel Mesulam ,Dick J Drost ,Joseph F Quinn ,Walter Martínez ,David G Clark ,Paul S Aisen ,Joanne Lord

doi:10.1038/ncomms13249

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.

Highlights

There is considerable debate whether Alzheimer’s disease (AD) originates in basal forebrain or entorhinal cortex
Our findings build on a varied body of histological evidence, which collectively point to both Ch4 and entorhinal cortex (EC) as early targets of AD pathology[8]
The proliferation of tangles and plaques in these structures leads to depletion of axons and cell loss, both of which contribute to microstructural decreases in volume[8,15,17,18]

Summary

Introduction

There is considerable debate whether Alzheimer’s disease (AD) originates in basal forebrain or entorhinal cortex. Regression-based mediation and conditional process models revealed that EC degeneration mediates the relationship between Ch4 integrity and memory impairment, and that AD pathology (Ab1–42) moderates this mediation effect.

Results

Conclusion