Evidence for a membrane lipid defect in Alzheimer disease.

We have previously shown that cells normally maintain their lipid metabolic pools at a critical composition, appropriate for spontaneous assembly of a stable membrane bilayer at their physiological temperature. When disease affects membrane lipids such that the new composition will only form a stable bilayer at a critical temperature (T*), which differs from the physiological value, membrane destabilization and hence cellular damage will necessarily ensue. We have previously tested this pathogenetic mechanism in metachromatic leukodystrophy, a disorder with a known primary lipid metabolic defect. In the present study, we found T* for cerebral cortex lipids from three Alzheimer disease (AD) patients ranged between 19 and 28 degrees C, independent of membrane protein composition. Control cortex lipids yielded a normal value for T* of 37 degrees C. Thus, one possible mechanism for neurodegeneration in AD is membrane destabilization secondary to a lipid compositional aberration, which shifts T* away from 37 degrees C. This lipid defect is brain region-specific as cerebellar lipids from the AD patients gave a normal value for T*. Studies aimed at delineating the nature of the biochemical anomaly are in progress.