Presenilin (PS) mutations enhance the production of the Aβ42 peptide that is derived from the amyloid precursor protein (APP). The pathway (s) by which the Aβ42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing