{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:02:57Z","timestamp":1790618577809,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["U24NS130600"],"award-info":[{"award-number":["U24NS130600"]}]},{"name":"National Institutes of Health","award":["5R21MH133239-02"],"award-info":[{"award-number":["5R21MH133239-02"]}]},{"name":"National Institutes of Health","award":["S10OD032285"],"award-info":[{"award-number":["S10OD032285"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>INTRODUCTION<\/jats:title>\n                  <jats:p>White matter (WM) functional activity, quantified as slow-4 fractional amplitude of low-frequency fluctuations (fALFF; 0.027\u20130.073 Hz), may reflect Alzheimer\u2019s disease (AD) pathology, but its utility relative to established structural imaging markers remains poorly characterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>We analyzed 369 ADNI-3 participants with baseline resting-state fMRI. Global WM slow-4 fALFF (JHU-20 atlas) was compared against hippocampal volume, entorhinal cortical thickness, FA, and MD across 11 outcomes: plasma biomarkers (pTau217, A\u03b242\/40, NfL, GFAP; n = 108), PET (amyloid Centiloid, tau SUVR, FDG; n = 66\u2013207), and cognition (MEM, EF, mPACC, MMSE; n \u2248 222\u2013225) using head-to-head benchmarking and variance decomposition.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>WM fALFF was significantly associated with GFAP (partial RZ = 5.35%), amyloid PET (partial RZ = 2.17%), tau PET (partial RZ = 3.52%), executive function (partial RZ = 2.61%), and mPACC (partial RZ = 3.53%). In trimmed models, fALFF explained unique variance in NfL and GFAP beyond FA and MD (unique \u0394RZ: 3.65% and 4.45%) \u2014 nearly 8-fold greater than DTI\u2019s unique contribution for NfL. Gray matter markers showed larger associations with cognition and PET pathology. The incremental value of fALFF was modality-specific: it persisted beyond DTI markers (NfL, GFAP, amyloid PET, executive function, mPACC) and beyond gray matter markers (NfL, GFAP), but in every domain \u2014 plasma included \u2014 fALFF was no longer significant when all five imaging markers were entered simultaneously.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>WM slow-4 fALFF captures neurodegeneration-related variance \u2014 particularly astroglial reactivity and axonal injury \u2014 incremental to DTI microstructure and partially independent of gray matter atrophy. These findings position WM functional activity as a complementary, non-invasive imaging marker in the multimodal AD biomarker landscape.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in Context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Evidence before this study<\/jats:title>\n                    <jats:p>White matter (WM) resting-state BOLD signals carry physiologically valid functional information. WM slow-4 fALFF is reduced in preclinical Alzheimer\u2019s disease (AD) and correlates with amyloid burden and cognition. Direct benchmarking against established structural imaging markers within matched samples has remained scarce.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Added value of this study<\/jats:title>\n                    <jats:p>In 369 ADNI-3 participants, we conducted a direct same-sample head-to-head comparison of global WM slow-4 fALFF versus hippocampal volume, entorhinal thickness, global FA, and MD across 11 pre-specified AD biomarker and cognitive outcomes. WM fALFF showed the largest covariate-adjusted association with GFAP (partial RZ = 5.35%) and uniquely explained \u223c8\u00d7 more NfL variance than DTI in trimmed models, contributing non-redundant functional information.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications of all the available evidence<\/jats:title>\n                    <jats:p>Global WM slow-4 fALFF, derived from standard resting-state fMRI, is a non-invasive complement to structural imaging that showed associations with markers of astroglial reactivity and neuroaxonal injury, and could augment multimodal AD biomarker panels without additional scanning cost.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.17.752468","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:35:19Z","timestamp":1790267719000},"source":"Crossref","is-referenced-by-count":0,"title":["White 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9260-6936","authenticated-orcid":false,"given":"Lu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory of Neuro Imaging (LONI), USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Alzheimer\u2019s Disease Neuroimaging 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