Postmortem analyses of senile plaques reveal numerous dystrophic processes in their vicinity. We used in vivo multiphoton microscopy of a transgenic model of Alzheimer disease (AD) to simultaneously image senile plaques and nearby neuronal processes. Plaques were labeled by immunofluorescent staining or thioflavine-S and neuronal processes were labeled with a fluorescent dextran conjugate. Imaging of 3-dimensional volumes in the vicinity of plaques revealed subtle changes in neurite geometry in or near diffuse plaques. By contrast, disruptions in neurite morphology, including dystrophic neurites immediately surrounding plaques as well as major alterations in neurite trajectories, were seen in association with thioflavine-S-positive plaques. Nearly half of all labeled processes that came within 50 μm of a thioflavine-S-positive plaque were altered, suggesting a fairly large “halo” of neuropil alterations that extend beyond the discrete border of a thioflavine-S plaque. These results support the hypothesis that compact thioflavine-S-positive plaques disrupt the neuropil in AD.