Lewy Body Pathology Modifies the Association Between APOE Genotype and Alzheimer’s Pathology

 

Rebecca Bernal1, Alice B. S. Nono Djotsa2,3, Obed Apochi4, Yannick N. Wadop1, Crystal D. Wiedner1, Biniyam A. Ayele5,6,7, Muralidharan Sargurupremraj1, Xueqiu Jian1, Alfred K. Njamnshi8,9, Cyrille Nkouonlack8,10, Jose E. Cavazos1,11, Sudha Seshadri1,11,12,13, Alfred Fonteh†, Bernard Fongang1,14,15, Agustin Ruiz*1,16,17,18, Margaret E. Flanagan*1,19, and Jayandra Jung Himali*1,12,13,16,20,21

on behalf of the African Initiative on Bioinformatics Online Training in Neurodegenerative Diseases (AI-BOND), The University of Texas Health Science Center at San Antonio, and South Texas Alzheimer's Disease Research Center.

 

1Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, Texas, USA, 2Department of Medicine Section of Health Services Research, Baylor College of Medicine, Houston, TX, USA, 3Center for Health Services Research & Development Center for Innovation Quality, Effectiveness and Safety (IQUEST), Michael E. DeBakey VA Medical Center, Houston, TX, USA, 4International Graduate School of Neuroscience IGSN, Ruhr University Bochum, Germany, 5John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida USA, 6Department of Neurology, College of Health Science, Addis Ababa University, Yared St. Addis Ababa, Ethiopia, 7Global Brain Health Institute (GBHI), University of California San Francisco (UCSF), San Francisco California, USA, 8Brain Research Africa Initiative (BRAIN) Geneva, Switzerland & Yaoundé, Obobogo Yaoundé Cameroon, 9Neuroscience Lab, Faculty of Medicine & Biomedical Sciences, The University of Yaoundé I, Yaoundé, Cameroon, 10Faculty of Health Sciences University of Buea Buea Cameroon, 11Department of Neurology UT Health San Antonio San Antonio Texas USA, 12Department of Neurology Boston University Chobanian & Avedisian School of Medicine Boston Massachusetts USA, 13 The Framingham Heart Study Framingham Massachusetts USA, 14Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America, 15Department of Population Health Sciences, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA, 16Ace Alzheimer Center Barcelona - Universitat Internacional de Catalunya. C/ Gran Via de Carles III, 85 bis, 08028 Barcelona, Spain, 17Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. C/ Melchor Fernández Almagro, 3, Fuencarral-El Pardo, 28029 Madrid, Spain, 18Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine. University of Texas Health Science Center, 19Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA, 20Department of Biostatistics Boston University School of Public Health Boston Massachusetts USA, 21Graduate School of Biomedical Sciences, UT Health San Antonio, San Antonio, TX, USA

*These authors contributed equally
† Deceased: [May 2026]. We honor Dr. Fonteh’s contributions to this research.

 

INTRODUCTION

Alzheimer’sdisease(AD)isaprogressiveneurodegenerativedisordercharacterizedbyamyloid-βplaquesandtauneurofibrillarytangles,andfrequentlyco-occurswithadditionalbrainco-pathologies,includingLewybodypathology(LBP).WhetherLBPmodifiestheassociationbetweenAPOEgenotypeandADneuropathologyremainsunclear.
WeexaminedwhetherLBPmodifiestheassociationbetweenAPOEgenotypeandAlzheimer-relatedneuropathologicmeasuresusingNationalAlzheimer’sCoordinatingCenter(NACC)dataset.
WehypothesizedthatLBPattenuatesthestrengthofassociationbetweenAPOEgenotypeandADneuropathologicburden,reflectinginteractionsbetweenco-occurringproteinopathies.

 

METHODS:

WeevaluatethemodifyingeffectofLBPontherelationshipbetweenAPOEgenotypeandADneuropathologicburden:ADneuropathologicchangescore,Thalphase,CERADneuriticplaquedensity,diffuseplaques,andBraaktanglestage.
WeincludedNACCautopsiedparticipantswithcompleteADneuropathologicandLBPassessments.
ParticipantswereclassifiedbyAPOEgenotypeasɛ4noncarriers(ɛ22,ɛ23,ɛ33),ɛ4heterozygote(ɛ24,ɛ34),orɛ4homozygotes(ɛ44).LBPwasdefinedaspresenceorabsence.
OrdinalorsimpleLogisticregressionmodelsadjustingforage,age-squared,sex,self-reportedancestry,andeducationwereused.Oddsratioscomparedɛ4heterozygotesandhomozygoteswithnoncarriers.
Statisticalsignificancewassetatfalsediscoveryrate-correctedα=0.05.

 

RESULTS:

Table 1. Participants Characteristic
		APOE ε4 Allele
Characteristic	Overall	ε33, ε22 ε23	ε24, ε34	ε44
N Age, years, mean (SD) Female Education, years Up to High School Some College Bachelor’s Degree Postgraduate Degree Self-reported Ancestry White Black or African American Other Hispanic or Latino Systolic Blood Pressure, mean (SD) Diastolic Blood Pressure, mean (SD) Smoking Status Lipid Lowering Medication Use Hypertension Treatment	7153 79 (12) 3405 (48)   1629 (23) 1298 (18) 2034 (28) 2192 (31)   6758 (95) 303 (4) 92 (1) 225 (3) 131 (20)   73 (11)   3207 (46) 2425 (35)   193 (3)	3998 80 (12) 1924 (48)   913 (23) 738 (18) 1113 (28) 1234 (31)   3800 (95) 134 (3) 64 (2) 140 (4) 131 (20)   73 (11)   1835 (47) 1296 (33)   109 (3)	2567 78 (11) 1218 (47)   592 (23) 442 (17) 756 (30) 777 (30)   2414 (94) 130 (5) 23 (1) 69 (3) 131 (20)   73 (11)   1127 (46) 911 (36)   70 (3)	588 75 (9) 263 (45)   124 (21) 118 (20) 165 (28) 181 (31)   544 (93) 39 (6) 5 (1) 16 (3) 130 (19)   74 (10)   245 (44) 218 (37)   14 (2)
Alzheimer’s Disease Neuropathologic Change (ADNC) No or low ADNC Intermediate or High ADNC Thal Phase Phase 0 Phase 1 and 2 Phase 3 Phase 4 Neuritic Plaques None Sparse Moderate Frequent Diffuse Plaques None Sparse Moderate Frequent Braak Tangle Stage Stage 0 Stage I and Stage II Stage III and Stage IV Stage V and Stage VI Other Brain Pathologies Lewy Body Pathology	1338 (31) 2921 (69)   582 (14) 618 (14) 510 (12) 2602 (60)   1695 (24) 917 (13) 1345 (18) 3196 (45)   998 (15) 854 (13) 1087 (16) 3675 (56)   383 (5) 1333 (19) 1716 (24) 3606 (51)   2006 (29)	1089 (46) 1286 (54)   530 (22) 458 (19) 334 (14) 1094 (45)   1427 (36) 558 (14) 765 (19) 1248 (31)   865 (24) 592 (16) 652 (18) 1569 (42)   319 (8) 1042 (27) 1114 (29) 1431 (37)   905 (23)	236 (15) 1298 (85)   49 (3) 149 (10) 158 (10) 1189 (77)   258 (11) 319 (12) 496 (19) 1494 (58)   123 (5) 233 (10) 371 (15) 1667 (70)   64 (3) 272 (11) 536 (21) 1675 (66)   850 (35)	13 (4) 337 (96)   3 (1) 11 (3) 18 (5) 319 (91)   10 (2) 40 (7) 84 (14) 454 (77)   10 (2) 29 (5) 64 (12) 439 (81)   0 19 (3) 66 (11) 500 (86)   251 (46)
Numbers are reported as n(%), unless otherwise stated.

 

CONCLUSIONS:

OurfindingssuggestthatLBP,modifiestheassociationbetweenAPOEε4andAD-relatedneuropathology:APOEε4heterozygotesandhomozygotesshowedsignificantassociationswithparenchymalamyloidandtaupathologybothinthepresenceandabsenceofLBP,butthestrengthoftheseassociationswasattenuatedamongindividualswithLBP.
FurtherclarifyingAPOE–LBPrelationshipsmayimproveunderstandingofhowco-occurringproteinopathyshapediseaseseverityandprogression,informclinicopathologicheterogeneityinmixedAD/LBD,andaidinthestratificationofparticipantsinbiomarkersandtherapeutictrialswhereco-pathologiesmayinfluenceAPOE-relatedassociations.

 

ACKNOWLEDGEMENTS:

Wethankallresearchvolunteersandourfunderswhomadethiseffortpossible.
TheNationalInstituteofAgingdesignatedSouthTexasAlzheimer'sDiseaseResearchCenter(P30AG066546).
TheNACCdatabaseisfundedbyNIA/NIHGrantU24
AG072122,andtheADRCsasthesourceofthedata.
TheBUILD-FSANIHUG3AG090675.
InmemoryofDr.Fonteh,whosecontributionstothisworkaregratefullyacknowledged.

 

REFERENCES:

1.Walkeretal.,2023.CognitiveresistancetoandresilienceagainstmultiplecomorbidneurodegenerativepathologiesandtheimpactofAPOEstatus.JournalofNeuropathology&ExperimentalNeurology.82(2):110-119
2.Robinsonetal.,2021.Thedevelopmentandconvergenceofco-pathologiesinAlzheimer'sdisease.Brain.144(3):953-962.
3.Talyanskyetal2023APOE-ε4andBIN1increaseriskofAlzheimer’sdiseasepathologybutnotspecificallyofLewybodypathology.JournalofActaNeuropathologicaCommunications11,149.
4.Alzheimer'sDiseaseResearchCenter.(n.d.).Uniformdataset(UDS)3.0:Researcherdatadictionary(RDD).UniversityofWashington.Retrievedfromhttps
://files.alz.washington.edu/documentation/uds3-rdd.pdf 
5.Alzheimer'sDiseaseResearchCenter.(n.d.).Researcherdatadictionary:Neuropsychology(RDD-NP).UniversityofWashington.Retrievedfromhttps
://files.alz.washington.edu/documentation/rdd-np.pdf