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<p>Longitudinal investigation of the Apolipoprotein E (APOE) genotype’s impact on Alzheimer’s disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation (“high Aβ accumulators”) were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.</p>

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Voxel-wise insights into early Alzheimer’s disease pathology progression: the association with APOE and memory decline

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  • 发表日期：

    2025年4月1日

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

摘要

Longitudinal investigation of the Apolipoprotein E (APOE) genotype’s impact on Alzheimer’s disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation (“high Aβ accumulators”) were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.