Identifying Distinct Spatiotemporal Patterns of Juxtacortical Microstructure in Alzheimer Disease Using Diffusion MRI–derived Free Water Fraction

Background The free water fraction (FWF) is a potential imaging marker in Alzheimer disease (AD). Purpose To evaluate juxtacortical FWF, its association with neuropathologic severity, and its spatiotemporal pattern using MRI and PET in participants with AD or normal cognition. Materials and Methods This secondary analysis of a prospective study was conducted from November 2021 to July 2024, including diffusion MRI to assess FWF, fluorine 18 (¹⁸F) florbetapir PET to assess amyloid-β (Aβ), and ¹⁸F-MK-6240 PET to assess tau accumulation. Two independent subtype and stage inference (SuStaIn) models analyzed only juxtacortical FWF change or integrated FWF and Aβ. Results A total of 359 participants (mean age, 69 years ± 8 [SD]; age range, 40-86 years; 223 female) were included (161 with normal cognition, 85 with mild cognitive impairment due to AD, and 113 with dementia due to AD). Compared with controls, participants with AD had increased FWF (false discovery rate [FDR]-corrected <i>P</i> < .001 to <i>P</i> = .049), which was associated with higher global cortical Aβ and tau deposition (<i>P</i> < .001 to <i>P</i> = .04 for Aβ; <i>P</i> < .001 to <i>P</i> = .01 for tau; all FDR-corrected). The first SuStaIn model identified two distinct spatiotemporal trajectories of FWF: The orbitofrontal-first subtype had smaller left and right hippocampus volumes (left, <i>b</i> = -0.1 and <i>P</i> = .007; right, <i>b</i> = -0.08 and <i>P</i> = .03) and worse cognitive performance (verbal fluency test, <i>b</i> = -0.21 and <i>P</i> = .01; shape-trail test part A, <i>b</i> = 0.16 and <i>P</i> < .001) compared with the precuneus-first subtype. The second SuStaIn model integrating FWF and Aβ identified two subtypes: The amyloid-first subtype had higher levels of amyloid deposition in the cortex (<i>b</i> = -0.3 and <i>P</i> < .001), whereas the FWF-first subtype had lower left cortical thickness (<i>b</i> = -0.05 and <i>P</i> = .01) and worse cognitive performance (verbal fluency test, <i>b</i> = -0.17 and <i>P</i> = .02; shape-trail test part A, <i>b</i> = 0.20 and <i>P</i> < .001). Conclusion Juxtacortical FWF was higher in participants with AD compared with cognitively normal controls and associated with Aβ, tau, and neurodegeneration biomarkers. Distinct spatiotemporal progression patterns of FWF had distinct cognitive performance profiles. Clinical trial registration no. NCT05623124 © RSNA, 2025 <i>Supplemental material is available for this article.</i> See also the editorial by Schoonheim in this issue.