Alterations in phospholipid metabolites are a characteristic abnormality of Alzheimer's disease (AD). Many of these alterations have been demonstrated by magnetic resonance spectroscopy (MRS) studies of postmortem tissue. Phosphodiesters appear to be elevated late in the disease and phosphomonoesters appear to be elevated early in the disease and then decrease. Second to aging, the most robust risk factor for AD identified to date is the presence of the E4 allele of apolipoprotein-E (Apo-E). Because apolipoproteins are intimately involved in lipid metabolism, this study was performed to determine if the presence of the Apo-E4 allele affects the abnormalities in phospholipid metabolites in AD brain. Perchloric acid extracts from 12 Apo-E 3/3, 31 3/4, 6 4/4 AD brains and 5 Apo-E 3/3 control brains were studied by both proton magnetic resonance spectroscopy and phosphorus-31 magnetic resonance spectroscopy. When the E4-positive AD samples were compared with the 3/3 AD samples, an exaggeration in both phosphomonoester and phosphodiester abnormalities was observed. The decrease in N-acetyl-L-aspartate (NAA) was also exaggerated. These results suggest membrane phospholipid metabolite alterations observed in AD are more severe in the presence of the Apo-E4 allele.