Cortical microstructural changes along the Alzheimer's disease continuum

Abstract Introduction Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). Methods We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging‐Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. Results Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. Discussion These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging as a surrogate marker of disease modification.