Ageing in Down's syndrome is accompanied by amyloid and neurofibrillary pathology the distribution of which replicates pathological features of Alzheimer's disease. With advancing age, an increasing proportion of Down's syndrome subjects >40 years old develop progressive cognitive impairment, resembling the cognitive profile of Alzheimer's disease. Based on these findings, Down's syndrome has been proposed as a model to study the predementia stages of Alzheimer's disease. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that non-demented Down's syndrome adults had significantly reduced hippocampus, entorhinal cortex and corpus callosum sizes with increasing age. In this study, we applied the automated and objective technique of voxel-based morphometry, implemented in SPM99, to the analysis of structural MRI from 27 non-demented Down's syndrome adults (mean age 41.1 years, 15 female). Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyrus), left occipital cortex (mainly lingual cortex), right precentral and left postcentral gyrus, left transverse temporal gyrus, and right parahippocampal gyrus. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal) and the anterior cingulate gyrus. Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of Down's syndrome. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to Alzheimer's disease-type pathology.