We measured somatostatin-like immunoreactivity, using a radioimmunoassay which does not cross react with cortistatin-like immunoreactivity, in postmortem frontal cortex (Brodmann area 9) from 32 patients, of different apolipoprotein E genotypes, and presenting with different degrees of cognitive impairment. Eleven subjects and eight patients presented with no (controls) or limited memory impairments (Borderline), respectively. Six patients with clinical criteria for possible Alzheimer's disease also presented with clinical or brain imaging of cerebrovascular disease (mixed dementia) and seven patients were classified as Alzheimer's disease (AD). In the 6 months preceeding their deaths, all subjects had been evaluated by Folstein's Mini Mental State examination (MMS). Sixty nine percent of patients with MMS >20 did not carry the epsilon 4 allele while 66% of patients with MMS <10 did. Somatostatin concentrations (ng/mg wet weight) were significantly lower in the patients carrying the epsilon 4 allele (E2/3: 0.71 +/- 0.05, n = 19 vs. E4: 0.42 +/- 0.06, n = 13; mean +/- SEM, P < 0.001). These results, which are reminiscent of those obtained on cholinergic markers, suggest that apolipoprotein E4 is involved in the somatostatinergic dysfunction early after the onset in AD.