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Small angle x-ray diffraction analysis of Alzheimer's disease (AD) lipid membranes reconstituted from cortical gray matter showed significant, reproducible structure changes relative to age-matched control samples. Specifically, there was an average 4 A reduction in the lipid bilayer width and marked changes in membrane electron density profiles of AD cortical samples. There were no significant structure differences in the membrane bilayers isolated from an unaffected region (cerebellum) of the AD brain. Lipid and protein analysis of six AD and six age-matched controls showed that the phospholipid:protein mass ratio was unchanged, but that the unesterified cholesterol:phospholipid (C:PL) mole ratio decreased by 30% in the AD temporal gyrus relative to age-matched controls. The C:PL mole ratio was not significantly different for samples prepared from cerebellum of AD versus control patients. X-ray diffraction analysis of a cholesterol-enriched AD sample demonstrated a virtual restoration of the normal membrane bilayer width and electron density profile, suggesting that the cholesterol deficit played a major role in the AD lipid membrane structure perturbation. Addition of beta-amyloid peptide to bovine brain phospholipid membranes significantly changed the electron density associated with the hydrocarbon core. Alterations in the composition and structure of the membrane bilayer may play an important role in the pathophysiology of AD by altering the activity and catabolism of membrane-bound proteins, including the beta-amyloid precursor protein.