The aberrant splicing isoform(PS2V), generated by exon 5 skipping of the Presenilin-2(PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease(sAD). We found PS2V is hypoxia-inducible in SK-N-SH cells and purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the High Mobility Group protein A1a: (HMGA1a). HMGA1a bound to a specific sequence on exon5, located upstream of the 5'-splice site. HMGA1a expression was induced by hypoxia. Over-expression of HMGA1a generated PS2V, through interference with U1snRNP binding to the 5'-splice site and caused exon5 skipping. HMGA1a levels were increased in brain from sAD patients. We propose a novel mechanism of sAD that involves HMGA1a-induced aberrant splicing of PS2 pre-mRNA in the absence of any mutations.