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

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.

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, Aβ42/40, 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.

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 ΔRZ: 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 (NfL, GFAP, amyloid PET, executive function, mPACC) and beyond gray matter markers (NfL, GFAP), but in every domain - plasma included - fALFF was no longer significant when all five imaging markers were entered simultaneously.

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.

Evidence before this study: White matter (WM) resting-state BOLD signals carry physiologically valid functional information. WM slow-4 fALFF is reduced in preclinical Alzheimer's disease (AD) and correlates with amyloid burden and cognition. Direct benchmarking against established structural imaging markers within matched samples has remained scarce.Added value of this study: 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 ∼8× more NfL variance than DTI in trimmed models, contributing non-redundant functional information.Implications of all the available evidence: 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.