A deficiency in somatostatin is the most consistently described neurochemical alteration in Alzheimer's disease (AD) attributable to intrinsic cortical neurons. Somatostatin-28 (SOM-28), and N-terminal-extended form of somatostatin, can be cleaved to form somatostatin-28 1–12(SOM-28 1–12) and somatostatin-14 (SOM-14). We have measured concentrations of SOM-28 1–12-like immunoreactivity in 8 cortical regions from 12 patients with AD and 13 controls. Significant reductions ( P < 0.001) were found in all cortical regions examined with the largest decrease in temporal lobe. Reductions were significantly correlated with decreases in somatostatin-14-like immunoreactivity in the same regions. The similar reductions of two prosomatostatin-derived peptides in AD cerebral cortex supports the contention that decreased somatostatin immunoreactivity in AD is caused by a degeneration of somatostatin cortical neurons and terminals.