jats:titleAbstract</jats:title>jats:secjats:titleBackground/Objective</jats:title>jats:pThe corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4‐repeat‐tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β‐amyloid status.</jats:p></jats:sec>jats:secjats:titleMethods</jats:title>jats:pTwenty‐five people with CBS, and 32 age‐/sex‐/education‐matched healthy controls participated. Regional synaptic density was estimated by [jats:sup11</jats:sup>C]UCB‐J non‐displaceable binding potential (BPjats:subND</jats:sub>), AD‐tau pathology by [jats:sup18</jats:sup>F]AV‐1451 BPjats:subND</jats:sub>, and gray matter volume by T1‐weighted magnetic resonance imaging. Participants with CBS had β‐amyloid imaging with jats:sup11</jats:sup>C‐labeled Pittsburgh Compound‐B ([jats:sup11</jats:sup>C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy‐rating‐scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPjats:subND</jats:sub> and gray matter volume between groups were assessed by ANOVA.</jats:p></jats:sec>jats:secjats:titleResults</jats:title>jats:pCompared to controls, patients with CBS had higher [jats:sup18</jats:sup>F]AV‐1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β‐amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side.</jats:p></jats:sec>jats:secjats:titleDiscussion</jats:title>jats:pDistinct patterns of [jats:sup11</jats:sup>C]UCB‐J and [jats:sup18</jats:sup>F]AV‐1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. jats:italicMovement Disorders</jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</jats:p></jats:sec>