White Matter Slow-4 fALFF as a Complementary Marker in the Multimodal Alzheimer's Disease Biomarker Landscape

INTRODUCTION White matter (WM) functional activity, quantified as slow-4 fractional amplitude of low-frequency fluctuations (fALFF; 0.027-0.073 Hz), may reflect Alzheimer's disease (AD) pathology, but its utility relative to established structural imaging markers remains poorly characterized. METHODS 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, Abeta42/40, NfL, GFAP; n = 108), PET (amyloid Centiloid, tau SUVR, FDG; n = 66-207), and cognition (MEM, EF, mPACC, MMSE; n = 222-225) using head-to-head benchmarking and variance decomposition. RESULTS WM fALFF was significantly associated with GFAP (partial R2 = 5.35%), amyloid PET (partial R2 = 2.17%), tau PET (partial R2 = 3.52%), executive function (partial R2 = 2.61%), and mPACC (partial R2 = 3.53%). In trimmed models, fALFF explained unique variance in NfL and GFAP beyond FA and MD (unique delta R2: 3.65% and 4.45%), nearly 8-fold greater than DTI's 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 for NfL, GFAP, amyloid PET, executive function, and mPACC, and beyond gray matter markers for NfL and GFAP, but in every domain, including plasma, fALFF was no longer significant when all five imaging markers were entered simultaneously. DISCUSSION WM slow-4 fALFF captures neurodegeneration-related variance, particularly astroglial reactivity and axonal injury, 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.