Abstract Background There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer’s disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer’s disease (FAD) provides the opportunity for investigation of presymptomatic change. We assessed early microstructural breakdown of cortical grey matter in FAD with diffusion-weighted MRI. Methods Diffusion-weighted and T1-weighed MRI were acquired in 38 FAD mutation carriers (17 symptomatic, 21 presymptomatic) and 39 controls. Mean diffusivity (MD) was calculated for six cortical regions previously identified as being particularly vulnerable to FAD-related neurodegeneration. Linear regression compared MD between symptomatic and presymptomatic carriers and controls, adjusting for age and sex. Spearman coefficients assessed associations between cortical MD and cortical thickness. Spearman coefficients also assessed associations between cortical MD and estimated years to/from onset (EYO). Across mutation carriers, linear regression assessed associations between MD and EYO, adjusting for cortical thickness. Results Compared with controls, cortical MD was higher in symptomatic mutation carriers (mean ± SD CDR = 0.88 ± 0.39) for all six regions (p