TY - JOUR
T1 - APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression
AU - Dincer, Aylin
AU - Chen, Charles D.
AU - McKay, Nicole S.
AU - Koenig, Lauren N.
AU - McCullough, Austin
AU - Flores, Shaney
AU - Keefe, Sarah J.
AU - Schultz, Stephanie A.
AU - Feldman, Rebecca L.
AU - Joseph-Mathurin, Nelly
AU - Hornbeck, Russ C.
AU - Cruchaga, Carlos
AU - Schindler, Suzanne E.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Fagan, Anne M.
AU - Benzinger, Tammie L.S.
AU - Gordon, Brian A.
N1 - Funding Information:
boardsorconsultsforGenentech,Denali,C2NDiagnostics,CajalNeurosciences,Takeda, Casma,andEliLilly.D.M.H.isaninventoron(i)apatententitled“Antibodiestotau, ”U.S.patent number9,834,596,licensedbytheW ashington UniversitytoC2NDiagnosticsonthe therapeuticuseofanti-tauantibodies;and(ii)apatentlicensedbytheW ashington University toEliLillyentitled“Humanizedantibodiesthatsequesteramyloidbetapeptide, ”U.S.patent number7,892,545,onahumanizedanti-Aβantibody.ThelaboratoryofD.M.H.receivesresearch grants from the NIH, Cure Alzheimer’s Fund, Tau Consortium, the JPB Foundation, Good Ventures, C2N Diagnostics, NextCure, and Denali. T .L.S.B. has investigator-initiated research funding fromthe NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation, and A vid Radiopharmaceuticals(awhollyownedsubsidiaryofEliLilly).T .L.S.B. participatesasasite investigatorinclinicaltrialssponsoredbyA vid Radiopharmaceuticals,EliLilly,Biogen,Eisai, Jaansen,andRoche;servesasanunpaidconsultanttoEisaiandSiemens;andisonthe Speaker’s Bureau for Biogen.
Funding Information:
Acknowledgments:W eacknowledgethealtruismoftheparticipantsandtheirfamiliesand contributions of the Knight ADRC research and support staff for contributions to this work. Withoutthecontributionandtimetheparticipantsgaveforthesestudies,thisworkwouldnot bepossible.Funding:Supportfortheseanalyseswaspro vided bytheNIH(P30AG066444, P01AG003991,andP01AG026276toJ.C.M.;K01AG053474toB.A.G.;andRF1AG053303and RF1AG044546 to C.C.), the Alzheimer’s Association (AARG-17-532945 to B.A.G.), the Alzheimer AssociationInternationalResearchProgram(AARFD-20-681815toN.J.-M.),andTheNational ScienceFoundation(DGE-1745038).Computationswereperformedusingthefacilitiesofthe W ashington UniversityCenterforHighPerformanceComputing,whichwerepartiallyfunded byNIHgrants1S10RR022984-01A1and1S10OD018091-01toW ashington University. Computing and research infrastructure were supported by UL1TR000448, P30NS098577, and R01EB009352.W ealsoacknowledgesupportfromtheHopeCenterforNeurologicalDisorders, theBarnes-JewishHospitalFoundationWillmanScholarA ward,andA vid Radiopharmaceuticals (awhollyownedsubsidiaryofEliLilly),whichprovidedtechnologytransferandprovided precursorforA V-1451. Ethicssta tement: Allparticipantsortheircaregiverssignedastandard informedconsentdocument,andtheInstitutionalReviewBoardatW ashington Universityin SaintLouisapprov ed allprocedures.ICMJEguidelineswerefollowedinpreparationofthe manuscript.Authorcontributions:Conceptionanddesign:A.D.andB.A.G.collaboratively conceivedthestudyaimsandgeneralapproachwithinputfromC.D.C.andN.S.M.Resources anddatacuration:A.D.,L.N.K.,S.F ., S.J.K.,R.L.F ., andR.C.H.processedtheneuroimagingdata. S.E.S.andA.M.F .ov ersaw CSFcollectionandprocessing.C.C.oversawAPOEgenotyping.J.C.M. oversawallclinicalassessments.Dataanalysisandinterpretation:A.D.performedtheregression analysesexaminingtheinfluenceofAPOEgenotypeonamyloid,tauPET ,CSFptau181,and atrophymeasureswithassistancefromB.A.G.C.D.C.assistedA.D.inthespatialcomparisons withAPOEmRNAexpr ession. A.D.generatedallofthefigures.N.S.M.,A.M.,N.J.-M.,C.C.,S.A.S., D.M.H.,andA.M.F .providedfeedbackandinterpretativecommentsonthedataanalyses. Manuscript writing: A.D. and B.A.G. Manuscript revision: All authors. Manuscript approval: All authors.Studysupervision:J.C.M.isthedirectoroftheKnightADRC,T .L.S.B. isthedirectorofthe NeuroimagingCore,andB.A.G.supervisedallelementsofthecurrentpaper.Competing interests:Thefollowingauthorshavenocompetinginterestsregardingthisstudy:A.D.,C.D.C., N.S.M., A.M., L.N.K., S.F ., S.J.K., R.L.F ., R.C.H., A.M.F ., J.C.M., and S.E.S. S.A.S. receives research support from the National Science Foundation. B.A.G. receives research support from the NIH and the Alzheimer’s Association N.J.-M. is supported partly by the Alzheimer’s Association International Research Program. C.C. received grants from the NIH and reports fees from GSK andTakeda.D.M.H.isacofounderofC2NDiagnosticsLLCandservesonthescientificadvisory
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2022/11/16
Y1 - 2022/11/16
N2 - The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.
AB - The apolipoprotein E (APOE) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau181). Three hundred fifty participants underwent imaging, and 270 had ptau181. We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau181. Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau181. This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.
UR - http://www.scopus.com/inward/record.url?scp=85142402261&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abl7646
DO - 10.1126/scitranslmed.abl7646
M3 - Article
C2 - 36383681
AN - SCOPUS:85142402261
SN - 1946-6234
VL - 14
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 671
M1 - eabl7646
ER -