Apolipoprotein E (ApoE), which is genetically polymorphic, is a constituent of different lipoproteins. Two variants, ApoE4(C112R) and ApoE4(L28P; C112R) have been linked to the risk of developing Alzheimer's disease. Transgenic mice carrying ApoE4(C112R) (AD71) and ApoE4(L28P; C112R) (AD61) were generated and compared to wild-type mice. The use of glial fibrillary acidic protein as promoter led to transgene expression mainly in glial cells but also in neurons. Transgene protein levels were approximately three-and-a-half-fold that of endogenous ApoE in the glial fibrillary acidic protein-ApoE4(C112R) (AD71) and nearly twofold in the glial fibrillary acidic protein-ApoE4(L28P; C112R) (AD61) mouse lines. Neither transgenic mouse differed from wild-type in cognitive tests at the age of approximately one-and-a-half years. The locomotor activity of AD61 mice was similar to controls, whereas AD71 mice exhibited a clearly reduced level of motor activity. Immunohistological and biochemical brain protein analyses revealed no difference between strains.Thus, in the absence of morphological changes over-expression of ApoE4(C112R) on a background of endogenous mouse ApoE, may result in behavioral deficits while for the ApoE4(L28P; C112R) transgene higher expression might be required or some compensatory mechanisms might protect these animals from the behavioral abnormalities.