Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3-28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0-7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7-7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms.