We analyzed an amino-terminal modification of p-amy-Ioid (A~) peptide in brain, using anti-Al~ antibodies that distinguish distinct molecular species. Examination of cortical sections from 28 aged individuals with a wide range in senile plaque density revealed that a molecular species distinct from the standard A~ is deposited in the brain in a dominant and differential manner. This modified AI~ peptide (A~ N3 (pE)) starts at the 3rd aminoterminal residue of the standard AI~, glutamate, converted to pyroglutamate through intramolecular dehy, dration. Because plaques composed of A~ N3 (pE) are present in equivalent or greater densities than those composed of standard Ap bearing the first aminoterminal residue (AId. l) and because deposition of the former species appears to precede deposition of the latter, as confirmed with specimens from Down's syndrome patients, the processes involved in A~ N3 (pE) production and retention may play an early and critical role in senile plaque formation.