The A4 amyloid precursor gene of Alzheimer's Disease (PreA4 gene, App gene, PAD gene) gives rise to three different transcripts, which are generated by alternative splicing. The three transcripts are PreA4695, PreA4751 and PreA4770, according to the number of amino-acids in the primary translation product. Previous expression studies did not discriminate between PreA4751 and PreA4770. We have analyzed the distribution of PreA4 transcripts in four cortical brain areas in a way that allows us the selective identification of each transcript. We used a sensitive S1 nuclease protection assay with a probe derived from PreA4770 cDNA. This radiolabeled probe gives rise to three specifically protected DNA fragments, each corresponding to one of the three PreA4 transcripts. These fragments could readily be resolved in a single lane of a denaturing polyacrylamide gel. PreA4 transcripts were quantified by scanning autoradiograms. In younger individuals PreA4695 mRNA is the dominant transcript with 55% (mean values). PreA4770 mRNA is the minor PreA4 transcript with less than 5% and PreA4751 ranges at 40%. The exception is observed in occipital cortex, where PreA4751 (50%) is higher than PreA695 (45%). A different situation was observed in older individuals. In the latter PreA4(695) transcripts are significantly reduced, with the exception of frontal cortex, whereas PreA4770 transcripts show an increase. PreA4751 has a constant level of 45% and becomes the dominant transcript.