The glial cytoplasmic inclusion provides a histological hallmark for multiple system atrophy, a group of neurodegenerative disorders including: striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Apolipoprotein E (APOE) genotype was determined by the polymerase chain reaction and restriction digestion of DNA extracted from frozen brain tissue from 22 patients (64.9 +/- 2.2 years) with clinically and neuropathologically verified multiple system atrophy (MSA). In addition, brain tissue from 36 age- and sex-matched patients who died with Alzheimer's disease (68.8 +/- 1.6 years) and 66 neurologically and psychiatrically normal subjects (66.6 +/- 1.8 years) was genotyped. The APOE e4 allele frequency in the Alzheimer's disease subjects was significantly increased (0.44, P < 0.001), as has been reported previously. The APOE e4 allele frequency of the MSA cases (0.11) was not significantly different from that of the control subjects (0.12). These data indicate that the APOE e4 allele is not a risk factor for multiple system atrophy.