The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aß in different brain regions.

ABSTRACT

Early-onset dominantly inherited forms of Alzheimer's disease (AD) are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and PSEN2, alter the APP processing and lead to an increased amyloid ß-peptide (Aß) 42/40 ratio. This, together with other studies on pathogenic mechanisms, show that Aß42 is a major player in the etiology of AD. Here, we present a clinical and neuropathological description of a Swedish family with an I143T mutation in the PSEN1 gene, which gives rise to a severe form of AD. We also performed an extensive investigation on the concentration and distribution of Aß species of different lengths in six brain regions from two mutation carriers. Our study showed that Aß42 and a longer peptide, Aß43, were present both in plaque cores and in total amyloid preparations, and were each clearly more frequent than Aß40 in all examined regions, as shown by both mass spectrometry and immunohistochemistry.