White matter integrity and its association with amyloid-PET and serum NfL in healthy APOE4 homozygotes, heterozygotes and non-carries

Except for aging, APOE ε4 allele ( APOE4 ) is the most important risk factor for sporadic Alzheimer’s disease. APOE4 carriers may have reduced capacity to recycle lipids, resulting in reduced white matter integrity. Here, we evaluated if white matter impairment measured by diffusion tensor imaging (DTI) differs between healthy individuals with different number of APOE4 alleles and if white matter impairment associates with brain beta-amyloid (Aβ) load and serum levels of neurofilament light chain (NfL). We studied 96 participants ( APOE4/4 , N = 20; APOE4/3 , N = 39; APOE3/3 , N = 37; mean age 70.7 (SD 5.22) years, 63% females) with brain MRI including a DTI sequence (N = 96), Aβ-PET (N = 89) and a venous blood sample for serum NfL concentration measurement (N = 88). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) in six a priori -selected white matter regions-of-interest (ROIs) were compared between the groups using ANCOVA, with sex and age as covariates. A voxel-weighted average of FA, MD, RD and AxD was calculated for each subject, and correlations with Aβ-PET and NfL levels were evaluated. APOE4/4 carriers exhibited higher MD and higher RD in the body of corpus callosum than APOE4/3 (p = 0.0053 and p = 0.0049, respectively) and APOE3/3 (p = 0.026 and p = 0.042). APOE4/4 carriers had higher AxD than APOE4/3 (p = 0.012) and APOE3/3 (p = 0.040) in the right cingulum adjacent to cingulate cortex. In the total sample, composite MD, RD and AxD positively correlated with cortical Aβ load (r = 0.26 to 0.33, p < 0.013 for all) and with serum NfL concentrations (r = 0.31 to 0.36, p < 0.0028 for all). In conclusion, reduced white matter integrity was detected in cognitively unimpaired APOE4/4 homozygotes compared to APOE4/3 and APOE3/3 carriers and reduced white matter integrity correlated with biomarkers of Alzheimer’s disease and neurodegeneration. White matter impairment seems to be an early phenomenon in the Alzheimer’s disease pathologic process in APOE4/4 homozygotes. Highlights ### Competing Interest Statement HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. ### Funding Statement This study received the following funding: LE was funded by the Paulo Foundation, the Juho Vainio Foundation and Finnish Governmental Research Funding (VTR). EP was supported by the Finnish Governmental Research Funding (VTR) for Turku University Hospital, The Yrjo Jahnsson Foundation, the Betania Foundation, the Paulo Foundation and the Uulo Arhio Memorial Foundation. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019 02397), the European Union s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG 71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809 2016862), the AD Strategic Fund and the Alzheimer s Association (#ADSF 21 831376C, #ADSF-21-831381C, and #ADSF 21 831377C), the Bluefield Project, the Olav Thon Foundation, the Erling Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2022 0270), the European Union s Horizon 2020 research and innovation programme under the Marie Skodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme Neurodegenerative Disease Research (JPND2021 00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI 1003). KB is supported by the Swedish Research Council (#2017 00915 and #2022 00732), the Swedish Alzheimer Foundation (#AF 930351, #AF 939721 and #AF 968270), Hjarnfonden, Sweden (#FO2017 0243 and #ALZ2022 0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (#ALFGBG 715986 and #ALFGBG 965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019 466-236), the Alzheimer s Association 2021 Zenith Award (ZEN 21 848495), and the Alzheimer s Association 2022 2025 Grant (SG 23 1038904 QC). JR has received grants from the Sigrid Juselius Foundation and Finnish Governmental Research Funding (VTR). AS was supported by the Emil Aaltonen foundation, the Paulo Foundation, the Orion Research Foundation sr, Finnish Governmental Research Funding (ERVA) for Turku University Hospital (#310962) and Research Council of Finland (#341059). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical Committee of the Hospital District of Southwest Finland gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available upon reasonable request to the authors