Journal article
Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer’s disease
Translational psychiatry
07/30/2026
DOI: 10.1038/s41398-026-04292-z
Abstract
White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.
Details
- Title: Subtitle
- Regional juxtacortical microstructural changes and gene expression provide insights into neurodegeneration in Alzheimer’s disease
- Creators
- Junfang Zhang - Shanghai Jiao Tong UniversityLipeng Sun - Shanghai Jiao Tong UniversityXinyuan Yang - Shanghai Jiao Tong UniversityLin Kang - Shanghai Jiao Tong UniversityYingting Zheng - Ruijin HospitalQi Huang - Fudan UniversityWei Xu - Ruijin HospitalYihui Guan - Fudan UniversityJun Liu - Shanghai Jiao Tong UniversityYulei Deng - Shanghai Jiao Tong UniversityFang Xie - Fudan UniversityXiaomeng Xu - Shanghai Jiao Tong UniversityBinyin Li - Taixing People's HospitalMichael W. Weiner - University of California, San FranciscoPaul Aisen - University of Southern CaliforniaRonald Petersen - Mayo Clinic in ArizonaClifford R. Jack - Mayo Clinic in ArizonaWilliam Jagust - University of California, BerkeleyJohn Q. Trojanowki - University of PennsylvaniaArthur W. Toga - University of Southern CaliforniaLaurel Beckett - University of California, DavisRobert C. Green - Hospitality HomesAndrew J. Saykin - Indiana University – Purdue University IndianapolisJohn C. Morris - Washington University in St. LouisRichard J. Perrin - Washington University in St. LouisLeslie M. Shaw - University of PennsylvaniaMaria Carrillo - Alzheimer's AssociationWilliam Potter - National Institute of Mental HealthLisa Barnes - Rush UniversityMarie Bernard - National Institutes of HealthHector González - University of California San DiegoCarole Ho - Denali Therapeutics (United States)John K. Hsiao - National Institutes of HealthJonathan Jackson - Massachusetts General HospitalEliezer Masliah - National Institutes of HealthDonna Masterman - Biogen (United States)Ozioma Okonkwo - University of Wisconsin–MadisonRichard Perrin - Washington University in St. LouisLaurie Ryan - National Institutes of HealthNina Silverberg - National Institutes of HealthAdam Fleisher - Eli Lilly (United States)Juliet Fockler - University of California, San FranciscoCat Conti - Northern California Institute for Research and EducationDallas Veitch - Northern California Institute for Research and EducationJohn Neuhaus - University of California, San FranciscoChengshi Jin - University of California, San FranciscoRachel Nosheny - University of California, San FranciscoMiriam Ashford - Northern California Institute for Research and EducationDerek Flenniken - Northern California Institute for Research and EducationAdrienne Kormos - Northern California Institute for Research and EducationGustavo Jimenez - University of Southern CaliforniaMichael Donohue - University of Southern CaliforniaDevon Gessert - University of Southern CaliforniaJennifer Salazar - University of Southern CaliforniaCaileigh Zimmerman - University of Southern CaliforniaYuliana Cabrera - University of Southern CaliforniaSarah Walter - University of Southern CaliforniaGarrett Miller - University of Southern CaliforniaGodfrey Coker - University of Southern CaliforniaTaylor Clanton - University of Southern CaliforniaLindsey Hergesheimer - University of Southern CaliforniaStephanie Smith - University of Southern CaliforniaOlusegun Adegoke - University of Southern CaliforniaPayam Mahboubi - University of Southern CaliforniaShelley Moore - University of Southern CaliforniaJeremy Pizzola - University of Southern CaliforniaElizabeth Shaffer - University of Southern CaliforniaBrittany Sloan - University of Southern CaliforniaDanielle Harvey - University of California, DavisBret Borowski - Mayo Clinic in ArizonaChad Ward - Mayo Clinic in ArizonaChristopher Schwarz - Mayo Clinic in ArizonaDavid Jones - Mayo Clinic in ArizonaJeff Gunter - Mayo Clinic in ArizonaKejal Kantarci - Mayo Clinic in ArizonaMatthew Senjem - Mayo Clinic in ArizonaPrashanthi Vemuri - Mayo Clinic in ArizonaRobert Reid - Mayo Clinic in ArizonaNick C. Fox - University College LondonIan Malone - University College LondonPaul Thompson - University of Southern CaliforniaSophia I. Thomopoulos - University of Southern CaliforniaTalia M. Nir - University of Southern CaliforniaNeda Jahanshad - University of Southern CaliforniaCharles DeCarli - University of California Davis Medical CenterAlexander Knaack - University of California, DavisEvan Fletcher - University of California Davis Medical CenterDuygu Tosun-TurgutStephanie Rossi Chen - Northern California Institute for Research and EducationMark Choe - Northern California Institute for Research and EducationKaren Crawford - University of Southern CaliforniaPaul A. Yushkevich - University of PennsylvaniaSandhitsu Das - University of PennsylvaniaRobert A. Koeppe - University of MichiganEric M. Reiman - Banner Alzheimer’s InstituteKewei Chen - Banner Alzheimer’s InstituteChet Mathis - University of PittsburghSusan Landau - University of California, BerkeleyNigel J. Cairns - Washington University in St. LouisErin Householder - Washington University in St. LouisErin Franklin - Washington University in St. LouisHaley Bernhardt - Washington University in St. LouisLisa Taylor-Reinwald - Washington University in St. LouisMagdalena Korecka - University of PennsylvaniaMichal Figurski - University of PennsylvaniaScott Neu - University of Southern CaliforniaKwangsik Nho - Indiana University BloomingtonShannon L. Risacher - Indiana University School of MedicineLiana G. Apostolova - Indiana University – Purdue University IndianapolisLi Shen - Indiana University BloomingtonTatiana M. Foroud - Indiana University BloomingtonKelly Nudelman - Indiana University BloomingtonKelley Faber - Indiana University BloomingtonKristi Wilmes - Indiana University School of MedicineLeon Thal - University of California San DiegoZaven Khachaturian - Prevent Alzheimer’s Disease 2020Lisa C. Silbert - Oregon Health & Science UniversityBetty Lind - Oregon Health & Science UniversityRachel Crissey - Oregon Health & Science UniversityJeffrey A. Kaye - Oregon Health & Science UniversityRaina Carter - Oregon Health & Science UniversitySara Dolen - Oregon Health & Science UniversityJoseph Quinn - Oregon Health & Science UniversityLon S. Schneider - University of Southern CaliforniaSonia Pawluczyk - University of Southern CaliforniaMauricio Becerra - University of Southern CaliforniaLiberty Teodoro - University of Southern CaliforniaKaren Dagerman - University of Southern CaliforniaBryan M. Spann - University of Southern CaliforniaJames Brewer - University of California San DiegoHelen Vanderswag - University of California San DiegoJaimie Ziolkowski - University of MichiganJudith L. Heidebrink - University of MichiganLisa Zbizek-Nulph - University of MichiganJoanne L. Lord - University of MichiganColleen S. Albers - Mayo Clinic in ArizonaDavid Knopman - Mayo Clinic in ArizonaKris Johnson - Brigham and Women's HospitalJavier Villanueva-Meyer - Baylor College of MedicineValory Pavlik - Baylor College of MedicineNathaniel Pacini - Baylor College of MedicineAshley Lamb - Baylor College of MedicineJoseph S. Kass - Baylor College of MedicineRachelle S. Doody - Baylor College of MedicineVictoria Shibley - Baylor College of MedicineMunir Chowdhury - Baylor College of MedicineSusan Rountree - Baylor College of MedicineMimi Dang - Baylor College of MedicineYaakov Stern - Columbia University Irving Medical CenterLawrence S. Honig - Columbia University Irving Medical CenterAkiva Mintz - Cleveland ClinicBeau Ances - Washington University in St. LouisDavid Winkfield - Washington University in St. LouisMaria Carroll - Washington University in St. LouisGeorgia Stobbs-Cucchi - Washington University in St. LouisAngela Oliver - Washington University in St. LouisMary L. Creech - Washington University in St. LouisMark A. Mintun - Washington University in St. LouisStacy Schneider - Washington University in St. LouisDavid Geldmacher - University of Alabama at BirminghamMarissa Natelson Love - University of Alabama at BirminghamRandall Griffith - University of Alabama at BirminghamDavid Clark - University of Alabama at BirminghamJohn Brockington - University of Alabama at BirminghamDaniel Marson - University of Alabama at BirminghamHillel Grossman - Icahn School of Medicine at Mount SinaiMartin A. Goldstein - Icahn School of Medicine at Mount SinaiJonathan Greenberg - Icahn School of Medicine at Mount SinaiEffie Mitsis - Icahn School of Medicine at Mount SinaiRaj C. Shah - Rush University Medical CenterMelissa Lamar - Rush University Medical CenterPatricia Samuels - Rush University Medical CenterRanjan DuaraMaria T. Greig-CustoRosemarie RodriguezMarilyn Albert - Johns Hopkins UniversityChiadi Onyike - Johns Hopkins UniversityLeonie Farrington - Johns Hopkins UniversityScott Rudow - Johns Hopkins UniversityRottislav Brichko - Johns Hopkins UniversityStephanie Kielb - Johns Hopkins UniversityAmanda Smith - University of South FloridaBalebail Ashok Raj - University of South FloridaKristin Fargher - University of South FloridaMartin Sadowski - New York UniversityThomas Wisniewski - New York UniversityMelanie Shulman - New York UniversityArline Faustin - New York UniversityJulia Rao - New York UniversityKaren M. Castro - New York UniversityAnaztasia Ulysse - New York UniversityShannon Chen - Northern California Institute for Research and EducationMohammed O. Sheikh - New York UniversityJamika Singleton-Garvin - New York UniversityP. Murali Doraiswamy - Duke Medical CenterJeffrey R. Petrella - Duke Medical CenterOlga James - Duke Medical CenterTerence Z. Wong - Duke Medical CenterSalvador Borges-Neto - Duke Medical CenterJason H. Karlawish - University of PennsylvaniaDavid A. Wolk - University of PennsylvaniaSanjeev Vaishnavi - University of PennsylvaniaChristopher M. Clark - University of PennsylvaniaSteven E. Arnold - University of PennsylvaniaCharles D. Smith - University of KentuckyGregory A. Jicha - University of KentuckyRiham El Khouli - University of KentuckyFlavius D. Raslau - University of KentuckyOscar L. Lopez - University of PittsburghMaryAnn Oakley - University of PittsburghDonna M. Simpson - University of PittsburghAnton P. Porsteinsson - University of Rochester MedicineKim Martin - University of Rochester MedicineNancy Kowalski - University of Rochester MedicineMelanie Keltz - University of Rochester MedicineBonnie S. Goldstein - University of Rochester MedicineKelly M. Makino - University of Rochester MedicineM. Saleem Ismail - University of Rochester MedicineConnie Brand - University of Rochester MedicineGaby Thai - University of California, IrvineAimee Pierce - University of California, IrvineBeatriz Yanez - University of California, IrvineElizabeth Sosa - University of California, IrvineMegan Witbracht - University of California, IrvineBrendan Kelley - The Ohio State UniversityTrung Nguyen - The University of Texas Southwestern Medical CenterKyle Womack - The University of Texas Southwestern Medical CenterDana Mathews - The University of Texas Southwestern Medical CenterMary Quiceno - The University of Texas Southwestern Medical CenterAllan I. Levey - Emory UniversityJames J. Lah - Emory UniversityIhab Hajjar - Emory UniversityJanet S. Cellar - Emory UniversityJeffrey M. Burns - University of Kansas Medical CenterRussell H. Swerdlow - University of Kansas Medical CenterWilliam M. Brooks - University of Kansas Medical CenterDaniel H. S. SilvermanSarah Kremen - University of California, Los AngelesLiana Apostolova - Indiana University – Purdue University IndianapolisKathleen Tingus - University of California, Los AngelesPo H. Lu - University of California, Los AngelesGeorge Bartzokis - University of California, Los AngelesEllen Woo - University of California, Los AngelesEdmond Teng - University of California, Los AngelesNeill R. Graff-Radford - Mayo Clinic in FloridaFrancine Parfitt - Mayo Clinic in FloridaKim Poki-Walker - Mayo Clinic in FloridaMartin R. Farlow - Indiana University BloomingtonAnn Marie Hake - Indiana University BloomingtonBrandy R. Matthews - Indiana University BloomingtonJared R. Brosch - Indiana University BloomingtonScott Herring - Indiana University BloomingtonChristopher H. van Dyck - Yale UniversityAdam P. Mecca - Yale UniversitySusan P. Good - Yale UniversityMartha G. MacAvoy - Yale UniversityRichard E. Carson - Yale UniversityPradeep Varma - Yale UniversityHoward Chertkow - Jewish General HospitalSusan Vaitekunis - Jewish General HospitalChris Hosein - Jewish General HospitalSandra Black - Sunnybrook Health Science CentreBojana Stefanovic - Sunnybrook Health Science CentreChris Chinthaka Heyn - Sunnybrook Health Science CentreGing-Yuek Robin HsiungEllen KimBenita MudgeVesna SossiHoward FeldmanMichele AssalyElizabeth FingerStephen PasternakIrina RachinskyAndrew KerteszDick DrostJohn RogersIan Grant - Northwestern UniversityBrittanie Muse - Northwestern UniversityEmily Rogalski - Northwestern UniversityJordan Robson - Northwestern UniversityM.-Marsel Mesulam - Northwestern UniversityDiana Kerwin - Northwestern UniversityChuang-Kuo Wu - Northwestern UniversityNancy Johnson - Northwestern UniversityKristine Lipowski - Northwestern UniversitySandra WeintraubBorna Bonakdarpour - Northwestern UniversityNunzio Pomara - Nathan Kline Institute for Psychiatric ResearchRaymundo Hernando - Nathan Kline Institute for Psychiatric ResearchAntero Sarrael - Nathan Kline Institute for Psychiatric ResearchHoward J. Rosen - University of California, San FranciscoBruce L. Miller - University of California, San FranciscoDavid Perry - University of California, San FranciscoRaymond Scott Turner - Georgetown UniversityKathleen Johnson - Brigham and Women's HospitalBrigid Reynolds - Georgetown UniversityKelly MCCann - Georgetown UniversityJessica Poe - Georgetown UniversityReisa A. Sperling - Brigham and Women's HospitalKeith A. Johnson - Brigham and Women's HospitalGad A. Marshall - Brigham and Women's HospitalChristine M. Belden - Banner Sun Health Research InstituteAlireza Atri - Banner Sun Health Research InstituteKelly A. Clark - University of PennsylvaniaEdward Zamrini - Banner Sun Health Research InstituteMarwan Sabbagh - Cleveland ClinicRonald Killiany - Boston UniversityRobert Stern - Boston UniversityJesse Mez - Boston UniversityNeil Kowall - Boston UniversityAndrew E. Budson - Boston UniversityThomas O. Obisesan - Howard UniversityOyonumo E. Ntekim - Howard UniversitySaba Wolday - Howard UniversityJaved I. Khan - Howard UniversityEvaristus Nwulia - Howard UniversitySheeba Nadarajah - Howard UniversityAlan Lerner - Case Western Reserve UniversityPaula Ogrocki - Case Western Reserve UniversityCurtis Tatsuoka - Case Western Reserve UniversityParianne Fatica - Case Western Reserve UniversityPauline Maillard - University of California, DavisJohn Olichney - University of California Davis Medical CenterOwen Carmichael - University of California Davis Medical CenterVernice Bates - Dent Neurologic InstituteHoracio Capote - Dent Neurologic InstituteMichelle Rainka - Dent Neurologic InstituteMichael Borrie - Parkwood InstituteT-Y Lee - Parkwood InstituteRob Bartha - Parkwood InstituteSterling Johnson - University of Wisconsin–MadisonSanjay Asthana - University of Wisconsin–MadisonCynthia M. Carlsson - University of Wisconsin–MadisonAllison Perrin - Banner Alzheimer’s InstituteAnna Burke - Banner Alzheimer’s InstituteDouglas W. Scharre - The Ohio State UniversityMaria Kataki - The Ohio State UniversityRawan Tarawneh - The Ohio State UniversityDavid Hart - Albany Medical Center HospitalEarl A. Zimmerman - Albany Medical Center HospitalDzintra Celmins - Albany Medical Center HospitalDelwyn D. Miller - University of IowaLaura L. Boles PontoKaren Ekstam Smith - University of IowaHristina Koleva - University of Iowa, PsychiatryHyungsub Shim - University of Iowa, NeurologyKi Won Nam - University of IowaSusan K. Schultz - University of California, DavisJeff D. Williamson - Wake Forest UniversitySuzanne Craft - Wake Forest UniversityJo Cleveland - Wake Forest UniversityMia Yang - Wake Forest UniversityKaycee M. Sink - Wake Forest UniversityBrian R. Ott - Providence CollegeJonathan Drake - Providence CollegeGeoffrey Tremont - Providence CollegeLori A. Daiello - Providence CollegeJonathan D. Drake - Providence CollegeAaron Ritter - Cleveland ClinicCharles Bernick - Cleveland ClinicDonna Munic - Cleveland ClinicAbigail O’Connelll - Roper St. Francis HealthcareJacobo Mintzer - Roper St. Francis HealthcareArthur Wiliams - Roper St. Francis HealthcareJoseph Masdeu - Houston MethodistJiong Shi - Barrow Neurological InstituteAngelica Garcia - Barrow Neurological InstitutePaul Newhouse - Vanderbilt University Medical CenterSteven Potkin - UC Irvine HealthStephen Salloway - Providence CollegePaul Malloy - Providence CollegeStephen Correia - Providence CollegeSmita Kittur - Hematology Oncology Associates of Central New YorkGodfrey D. Pearlson - Hartford HospitalKaren Blank - Hartford HospitalKaren Anderson - Hartford HospitalLaura A. Flashman - Dartmouth–Hitchcock Medical CenterMarc Seltzer - Dartmouth–Hitchcock Medical CenterMary L. Hynes - Dartmouth–Hitchcock Medical CenterRobert B. Santulli - Dartmouth–Hitchcock Medical CenterNorman Relkin - Cornell UniversityGloria Chiang - Cornell UniversityMichael Lin - Cornell UniversityLisa Ravdin - Cornell UniversityAthena Lee - Cornell UniversityRon Petersen - Mayo Clinic in ArizonaThomas Neylan - University of California, San FranciscoJordan Grafman - Northwestern UniversityTom Montine - University of WashingtonSarah Danowski - University of Southern CaliforniaCatherine Nguyen-Barrera - University of Southern CaliforniaShannon Finley - Shanghai Jiao Tong UniversityMatthew Bernstein - University of California, San FranciscoNorm Foster - University of UtahSungeun Kim - Indiana University BloomingtonAjay Sood - Rush University Medical CenterKimberly S. Blanchard - Rush University Medical CenterDebra Fleischman - Rush University Medical CenterMaria T. GreigBonnie Goldstein - University of Rochester MedicineKimberly S. Martin - University of Rochester MedicineChristopher Reist - University of California, IrvineCarl Sadowsky - Palm Beach NeurologyWalter Martinez - Palm Beach NeurologyTeresa Villena - Palm Beach NeurologyHoward Rosen - University of California, San FranciscoElaine R. Peskind - University of WashingtonEric C. Petrie - University of WashingtonGail Li - University of WashingtonJerome Yesavage - Stanford UniversityJoy L. Taylor - Stanford UniversitySteven Chao - Stanford UniversityJaila Coleman - Stanford UniversityJessica D. White - Stanford UniversityBarton Lane - Stanford UniversityAllyson Rosen - Stanford UniversityJared Tinklenberg - Stanford UniversityGustavo Jimenez-Maggiora - University of Southern CaliforniaErin Drake - Houghton Mifflin Harcourt (United States)Mike Donohue - University of Southern CaliforniaCraig Nelson - University of California, San FranciscoDavid Bickford - University of California, San FranciscoMeryl Butters - University of PittsburghMichelle Zmuda - University of PittsburghMatt Senjem - Mayo Clinic in ArizonaDenise Reyes - Mayo Clinic in ArizonaKelley M. Faber - Indiana University BloomingtonKelly N. Nudelman - Indiana University BloomingtonYiu Ho Au - University of California, San FranciscoKelly Scherer - University of California, San FranciscoDaniel Catalinotto - University of California, San FranciscoSamuel Stark - University of California, San FranciscoElise Ong - University of California, San FranciscoDariella Fernandez - University of California, San FranciscoAlzheimer’s Disease Neuroimaging Initiative
- Resource Type
- Journal article
- Publication Details
- Translational psychiatry
- DOI
- 10.1038/s41398-026-04292-z
- ISSN
- 2158-3188
- eISSN
- 2158-3188
- Publisher
- Springer Nature
- Language
- English
- Electronic publication date
- 07/30/2026
- Academic Unit
- Neurology; Psychiatry
- Record Identifier
- 9985217067402771
Metrics
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