Free-water imaging predicts cognitive decline and clinical progression in cognitively normal older adults.

The main objective of this study was to investigate the role of cortical free-water (cFW) imaging as a sensitive biomarker for tau-related microstructural injury and cognitive decline in preclinical Alzheimer's disease (AD). We aimed to determine whether cFW levels, derived from diffusion MRI, could predict cognitive decline and clinical progression independent of amyloid burden and other traditional imaging biomarkers. We analyzed data from 276 cognitively normal older adults from the Harvard Aging Brain Study (HABS). Participants underwent diffusion MRI, amyloid and tau PET imaging, and neuropsychological assessments. cFW was derived using bi-tensor modeling, and statistical analyses including general linear models and Cox proportional hazards models were used to evaluate associations between cFW, tau and amyloid burden, cognitive decline (Preclinical Alzheimer Cognitive Composite-5, PACC5), and progression to mild cognitive impairment (CDR = 0.5), adjusting for age, sex, education, cortical thickness, and amyloid status. Elevated cFW levels were significantly associated with regional tau deposition, particularly in the entorhinal cortex and fusiform gyrus, but not with global amyloid burden. Higher cFW predicted faster cognitive decline and greater risk of clinical progression, independent of amyloid status. Interaction analyses revealed that elevated cFW, in combination with either amyloid or tau, amplified the risk of cognitive decline. Cortical free-water imaging serves as a sensitive, non-invasive biomarker for tau-related microstructural damage and early cognitive decline in cognitively normal adults. This imaging technique offers enhanced early detection and risk stratification, facilitating earlier intervention and improving therapeutic outcomes.