Brain lipid changes have been reported in Alzheimer disease (AD), but their basis is not understood. In fibroblasts bearing presenilin-1 mutations, brain phospholipid composition was the same as in control fibroblasts. Cholesterol and the cholesterol/phospholipid levels also were unaltered. Thus, if AD lipid changes occur, they may be restricted to brain.In AD brain, the apolipoprotein E4 (ApoE4) genotype was associated with reduced phospholipase A2 activity in frontal cortex and hippocampus, but not in cerebellum, consistent with dysfunction of phospholipid metabolism in pathologically affected but not unaffected brain regions in AD.Phospholipase A2 activity was measured in brain regions from 3- and 20-month old ApoE-deficient mice (these mice have learning deficits). In 20-mo but not 3-mo old mice, enzyme activity was reduced by 20% in the hippocampus (known to mediate memory) but not in other brain regions, suggesting a regional role of ApoE in brain phospholipid metabolism. Additionally, ethanolamine plasmalogen levels were found to be reduced by 37% in brains from older Down syndrome (DS) subjects compared with control brains. The changes do not appear to reflect AD neuropathology in DS, as they also were found in the cerebellum, where AD neuropathology is absent. They likely reflect loss of dendrites, sites of plasmalogen accumulation, underlying mental retardation in DS.
