{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:09:57Z","timestamp":1792523397920,"version":"4.5.0"},"posted":{"date-parts":[[2025,8,15]]},"group-title":"Radiology and Imaging","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>With global dementia rates rising sharply, there is an urgent need for sensitive biomarkers to detect cognitive changes and predict dementia risk. White matter degeneration, especially axonal loss, is increasingly recognized as an early hallmark of Alzheimer\u2019s disease (AD), but its temporal trajectory and its relationship with cognition have not been established. We utilized a novel MRI-derived Axonal Density Index (ADI) to longitudinally investigate axonal degeneration and cognitive decline in the ADNI cohort. Linear mixed-effects models showed cognitively impaired individuals had lower baseline ADI and faster axonal degeneration compared to cognitively normal subjects. In cognitively impaired individuals, higher baseline ADI predicted slower prospective cognitive deterioration and lower dementia risk, while greater longitudinal ADI declines correlated with cognitive worsening and increased dementia risk. Notably, ADI outperformed cerebrospinal fluid biomarkers of AD pathology in predicting cognitive outcomes. Our original findings position axonal degeneration as an early AD feature and ADI as a promising biomarker for early detection, disease phenotyping and monitoring, and intervention targets.<\/jats:p>","DOI":"10.1101\/2025.08.13.25333630","type":"posted-content","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T19:45:13Z","timestamp":1755287113000},"source":"Crossref","is-referenced-by-count":1,"title":["Axonal Degeneration Across the Alzheimer\u2019s Disease Spectrum: A Longitudinal MRI and Fluid Biomarker Study"],"prefix":"10.64898","author":[{"given":"Zhaoyuan","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Laporte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander Y.","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonghyun","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam Y.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"de Rouen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaliya","family":"Taranath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"de Cabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine M.","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Ferrucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustapha","family":"Bouhrara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.1","doi-asserted-by":"crossref","first-page":"25741","DOI":"10.1038\/s41598-024-75204-8","article-title":"Critical assessment of anti-amyloid-\u03b2 monoclonal antibodies effects in Alzheimer\u2019s disease: a systematic review and meta-analysis highlighting target engagement and clinical meaningfulness","volume":"14","year":"2024","journal-title":"Scientific Reports"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.2","doi-asserted-by":"crossref","first-page":"e1559","DOI":"10.1002\/ctm2.1559","article-title":"Amyloid-beta (A\u03b2)-targeting monoclonal antibody trials in early Alzheimer\u2019s disease-Clinical outcome with gantenerumab","volume":"14","year":"2024","journal-title":"Clin Transl Med"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.3","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-025-00465-w","article-title":"Second-generation anti-amyloid monoclonal antibodies for Alzheimer\u2019s disease: current landscape and future perspectives","volume":"14","year":"2025","journal-title":"Translational Neurodegeneration"},{"key":"2025081806500702000_2025.08.13.25333630v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"2025081806500702000_2025.08.13.25333630v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.032"},{"key":"2025081806500702000_2025.08.13.25333630v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002923"},{"key":"2025081806500702000_2025.08.13.25333630v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad159"},{"key":"2025081806500702000_2025.08.13.25333630v1.8","doi-asserted-by":"crossref","unstructured":"Morris GP , Clark IA , Vissel B . Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer\u2019s disease. Acta Neuropathol Commun. 2014;2:135.","DOI":"10.1186\/PREACCEPT-1342777270140958"},{"key":"2025081806500702000_2025.08.13.25333630v1.9","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy229"},{"key":"2025081806500702000_2025.08.13.25333630v1.10","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13371"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40478-018-0515-3","article-title":"White matter changes in Alzheimer\u2019s disease: a focus on myelin and oligodendrocytes","volume":"6","year":"2018","journal-title":"Acta Neuropathologica Communications"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.12","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40478-018-0515-3","article-title":"White matter changes in Alzheimer\u2019s disease: a focus on myelin and oligodendrocytes","volume":"6","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"2025081806500702000_2025.08.13.25333630v1.13","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-013-0415-7"},{"key":"2025081806500702000_2025.08.13.25333630v1.14","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-022-01030-7"},{"key":"2025081806500702000_2025.08.13.25333630v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22432"},{"key":"2025081806500702000_2025.08.13.25333630v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.05.012"},{"key":"2025081806500702000_2025.08.13.25333630v1.17","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0635-8"},{"key":"2025081806500702000_2025.08.13.25333630v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1195-2"},{"key":"2025081806500702000_2025.08.13.25333630v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12618"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.20","doi-asserted-by":"crossref","first-page":"3231","DOI":"10.1038\/s41467-025-58466-2","article-title":"Spatial transcriptomics of the aging mouse brain reveals origins of inflammation in the white matter","volume":"16","year":"2025","journal-title":"Nature Communications"},{"key":"2025081806500702000_2025.08.13.25333630v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-010-0657-2"},{"key":"2025081806500702000_2025.08.13.25333630v1.22","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20734"},{"issue":"15","key":"2025081806500702000_2025.08.13.25333630v1.23","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1016\/j.neuron.2021.05.034","article-title":"Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms","volume":"109","year":"2021","journal-title":"Neuron"},{"issue":"12","key":"2025081806500702000_2025.08.13.25333630v1.24","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.jalz.2015.05.014","article-title":"The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment","volume":"11","year":"2015","journal-title":"Alzheimer\u2019s & dementia : the journal of the Alzheimer\u2019s Association"},{"key":"2025081806500702000_2025.08.13.25333630v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12040"},{"key":"2025081806500702000_2025.08.13.25333630v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24647"},{"key":"2025081806500702000_2025.08.13.25333630v1.27","doi-asserted-by":"crossref","unstructured":"Gong Z , Bilgel M , An Y , Bergeron CM , Bergeron J , Zukley L , et al. Cerebral white matter myelination is associated with longitudinal changes in processing speed across the adult lifespan. Brain Communications. 2024;6(6).","DOI":"10.1093\/braincomms\/fcae412"},{"key":"2025081806500702000_2025.08.13.25333630v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12968"},{"key":"2025081806500702000_2025.08.13.25333630v1.29","doi-asserted-by":"crossref","unstructured":"Gong Z , Faulkner ME , Akhonda MABS , Guo A , Bae J , Laporte JP , et al. White matter integrity and motor function: a link between cerebral myelination and longitudinal changes in gait speed in aging. GeroScience. 2024.","DOI":"10.1007\/s11357-024-01392-w"},{"key":"2025081806500702000_2025.08.13.25333630v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06120-6"},{"key":"2025081806500702000_2025.08.13.25333630v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2797"},{"key":"2025081806500702000_2025.08.13.25333630v1.32","doi-asserted-by":"crossref","first-page":"1264448","DOI":"10.3389\/fnagi.2023.1264448","article-title":"Alzheimer\u2019s disease: an axonal injury disease?","volume":"15","year":"2023","journal-title":"Front Aging Neurosci"},{"key":"2025081806500702000_2025.08.13.25333630v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02321-7"},{"issue":"3","key":"2025081806500702000_2025.08.13.25333630v1.34","doi-asserted-by":"crossref","first-page":"e12627","DOI":"10.1002\/dad2.12627","article-title":"NODDI in gray matter is a sensitive marker of aging and early AD changes","volume":"16","year":"2024","journal-title":"Alzheimers Dement (Amst"},{"key":"2025081806500702000_2025.08.13.25333630v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-023-02215-8"},{"key":"2025081806500702000_2025.08.13.25333630v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.03.072"},{"key":"2025081806500702000_2025.08.13.25333630v1.37","doi-asserted-by":"crossref","unstructured":"Coelho S , Baete SH , Lemberskiy G , Ades-Aron B , Barrol G , Veraart J , et al. Reproducibility of the Standard Model of diffusion in white matter on clinical MRI systems. NeuroImage. 2022;257:119290.","DOI":"10.1016\/j.neuroimage.2022.119290"},{"key":"2025081806500702000_2025.08.13.25333630v1.38","doi-asserted-by":"crossref","unstructured":"Alsameen MH , Gong Z , Qian W , Kiely M , Triebswetter C , Bergeron CM , et al. C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter. Front Neurol. 2023;14:1205426.","DOI":"10.3389\/fneur.2023.1205426"},{"key":"2025081806500702000_2025.08.13.25333630v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.06.003"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.40","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13195-023-01281-y","article-title":"Neuroimaging of tissue microstructure as a marker of neurodegeneration in the AT(N) framework: defining abnormal neurodegeneration and improving prediction of clinical status","volume":"15","year":"2023","journal-title":"Alzheimer\u2019s Research & Therapy"},{"key":"2025081806500702000_2025.08.13.25333630v1.41","doi-asserted-by":"crossref","unstructured":"Parker DM , Adams JN , Kim S , McMillan L , Yassa MA . NODDI-derived measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer\u2019s disease pathology and cognitive outcomes. bioRxiv. 2023.","DOI":"10.1101\/2023.10.11.561946"},{"issue":"4","key":"2025081806500702000_2025.08.13.25333630v1.42","doi-asserted-by":"crossref","first-page":"fcab272","DOI":"10.1093\/braincomms\/fcab272","article-title":"Loss and dispersion of superficial white matter in Alzheimer\u2019s disease: a diffusion MRI study","volume":"3","year":"2021","journal-title":"Brain Commun"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.43","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40478-022-01319-6","article-title":"White matter damage due to vascular, tau, and TDP-43 pathologies and its relevance to cognition","volume":"10","year":"2022","journal-title":"Acta Neuropathologica Communications"},{"issue":"2","key":"2025081806500702000_2025.08.13.25333630v1.44","doi-asserted-by":"crossref","first-page":"100019","DOI":"10.1016\/j.cellin.2022.100019","article-title":"NAD+-dependent mechanism of pathological axon degeneration","volume":"1","year":"2022","journal-title":"Cell Insight"},{"key":"2025081806500702000_2025.08.13.25333630v1.45","doi-asserted-by":"crossref","unstructured":"Wang B , Huang M , Shang D , Yan X , Zhao B , Zhang X . Mitochondrial Behavior in Axon Degeneration and Regeneration. Front Aging Neurosci. 2021;13:650038.","DOI":"10.3389\/fnagi.2021.650038"},{"key":"2025081806500702000_2025.08.13.25333630v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2012.04.001"},{"key":"2025081806500702000_2025.08.13.25333630v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10251"},{"key":"2025081806500702000_2025.08.13.25333630v1.48","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E04-05-0401"},{"key":"2025081806500702000_2025.08.13.25333630v1.49","doi-asserted-by":"crossref","unstructured":"Salvadores N , Ger\u00f3nimo-Olvera C , Court FA . Axonal Degeneration in AD: The Contribution of A\u03b2 and Tau. Front Aging Neurosci. 2020;12:581767.","DOI":"10.3389\/fnagi.2020.581767"},{"issue":"2","key":"2025081806500702000_2025.08.13.25333630v1.50","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/med.21534","article-title":"Involvement of calpain in the neuropathogenesis of Alzheimer\u2019s disease","volume":"39","year":"2019","journal-title":"Med Res Rev"},{"key":"2025081806500702000_2025.08.13.25333630v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.03.009"},{"key":"2025081806500702000_2025.08.13.25333630v1.52","doi-asserted-by":"crossref","unstructured":"Faulkner ME , Gong Z , Guo A , Laporte JP , Bae J , Bouhrara M . Harnessing myelin water fraction as an imaging biomarker of human cerebral aging, neurodegenerative diseases, and risk factors influencing myelination: A review. Journal of neurochemistry. 2024.","DOI":"10.1111\/jnc.16170"},{"issue":"5","key":"2025081806500702000_2025.08.13.25333630v1.53","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jalz.2009.11.003","article-title":"White matter is altered with parental family history of Alzheimer\u2019s disease","volume":"6","year":"2010","journal-title":"Alzheimer\u2019s & dementia : the journal of the Alzheimer\u2019s Association"},{"key":"2025081806500702000_2025.08.13.25333630v1.54","doi-asserted-by":"publisher","DOI":"10.1080\/87565641003696775"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.55","doi-asserted-by":"crossref","first-page":"e12381","DOI":"10.1002\/dad2.12381","article-title":"Associations between diffusion MRI microstructure and cerebrospinal fluid markers of Alzheimer\u2019s disease pathology and neurodegeneration along the Alzheimer\u2019s disease continuum","volume":"14","year":"2022","journal-title":". Alzheimers Dement (Amst"},{"key":"2025081806500702000_2025.08.13.25333630v1.56","doi-asserted-by":"crossref","unstructured":"Guo AY , Laporte JP , Singh K , Bae J , Bergeron K , de Rouen A , et al. Machine Learning Classification of Mild Cognitive Impairment using Advanced Multi-Shell Diffusion MRI and CSF Biomarkers. medRxiv. 2025:2025.02.27.25322792.","DOI":"10.1101\/2025.02.27.25322792"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.57","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13195-023-01281-y","article-title":"Neuroimaging of tissue microstructure as a marker of neurodegeneration in the AT(N) framework: defining abnormal neurodegeneration and improving prediction of clinical status","volume":"15","year":"2023","journal-title":"Alzheimers Res Ther"},{"key":"2025081806500702000_2025.08.13.25333630v1.58","doi-asserted-by":"crossref","unstructured":"Horie K , Salvad\u00f3 G , Koppisetti RK , Janelidze S , Barth\u00e9lemy NR , He Y , et al. Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer\u2019s disease. Nature Medicine. 2025.","DOI":"10.1038\/s41591-025-03617-7"},{"key":"2025081806500702000_2025.08.13.25333630v1.59","doi-asserted-by":"crossref","unstructured":"Oh HS-H , Urey DY , Karlsson L , Zhu Z , Shen Y , Farinas A , et al. A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer\u2019s disease. Nature Medicine. 2025.","DOI":"10.1038\/s41591-025-03565-2"},{"issue":"2","key":"2025081806500702000_2025.08.13.25333630v1.60","doi-asserted-by":"crossref","first-page":"e14549","DOI":"10.1002\/alz.14549","article-title":"The Dementia SomaSignal Test (dSST): A plasma proteomic predictor of 20-year dementia risk","volume":"21","year":"2025","journal-title":"Alzheimers Dement"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.61","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13024-024-00772-2","article-title":"Proteomic analysis of APOEepsilon4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience","volume":"19","year":"2024","journal-title":"Mol Neurodegener"},{"issue":"S2","key":"2025081806500702000_2025.08.13.25333630v1.62","doi-asserted-by":"crossref","first-page":"e092515","DOI":"10.1002\/alz.092515","article-title":"Plasma ADRD biomarkers predict longitudinal declines in intra-network functional brain connectivity, and baseline functional connectivity predicts longitudinal cognition","volume":"20","year":"2024","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2025081806500702000_2025.08.13.25333630v1.63","doi-asserted-by":"crossref","unstructured":"Walker KA , Duggan MR , Gong Z , Dark HE , Laporte JP , Faulkner ME , et al. MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging. Annals of clinical and translational neurology. 2023.","DOI":"10.1002\/acn3.51730"},{"issue":"1","key":"2025081806500702000_2025.08.13.25333630v1.64","first-page":"41","volume":"74","year":"2017","journal-title":"Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease. JAMA Neurol"},{"key":"2025081806500702000_2025.08.13.25333630v1.65","doi-asserted-by":"crossref","unstructured":"Wang Z , Chen Y , Gong K , Zhao B , Ning Y , Chen M , et al. Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages. Cell Rep Med. 2025:102031.","DOI":"10.1016\/j.xcrm.2025.102031"},{"key":"2025081806500702000_2025.08.13.25333630v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.09.015"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.13.25333630","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:43:20Z","timestamp":1768509800000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.08.13.25333630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":66,"URL":"https:\/\/doi.org\/10.1101\/2025.08.13.25333630","relation":{},"subject":[],"published":{"date-parts":[[2025,8,15]]},"subtype":"preprint"}}