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We propose and detail a deformation-based morphometry computational framework, called Longitudinal Log-Demons Framework (LLDF), to estimate the longitudinal brain deformations from image data series, transport them in a common space and perform statistical group-wise analyses. It is based on freely available software and tools, and consists of three main steps: (i) Pre-processing, (ii) Position correction, and (iii) Non-linear deformation analysis. It is based on the LOC log-Demons non-linear symmetric diffeomorphic registration algorithm with an additional modulation of the similarity term using a confidence mask to increase the robustness with respect to brain boundary intensity artifacts. The pipeline is exemplified on the longitudinal Open Access Series of Imaging Studies (OASIS) database and all the parameters values are given so that the study can be reproduced. We investigate the group-wise differences between the patients with Alzheimer’s disease and the healthy control group, and show that the proposed pipeline increases the sensitivity with no decrease in the specificity of the statistical study done on the longitudinal deformations.