P1–203: The effects of gene mutations on the cerebrospinal fluid levels of soluble amyloid precursor proteins in familial Alzheimer's disease

Abstract

The amyloid precursor protein (APP) is processed either by α -secretase in a nonamyloidogenic pathway, generating sAPP α, or in an amyloidogenic pathway where BACE1 cleaves APP releasing sAPPβ. Studies have shown that sAPP α and sAPPβ are unaltered or mildly elevated in MCI and sporadic AD. We compared the levels of sAPP α and sAPPβ between carriers of mutations leading to familial Alzheimer disease (PSEN1, APPswe and APParc) and non-carriers from the same families. Cerebrospinal fluid samples were collected from a total of 36 subjects, 6 PSEN1 mutation carriers, 9 APPswe carriers, 4 APParc carriers and 17 non-carriers (table 1). Concentrations of sAPP α and sAPPβ were determined using the MSD sAPP α/sAPP b Multiplex assay (Meso Scale Discovery, Gaithersburg, Maryland, USA). The levels of sAPP α and sAPPβ in mutation carriers (M+) and non-carriers (M-) were compared using the Mann-Whitney U-test. When comparing all mutation carriers with non-carriers, or PSEN1 carriers with non-carriers, there was no significant difference in the levels of sAPP α or sAPPβ. The carriers of the APPswe mutation however had significantly lower levels of both sAPP α and sAPPβ compared to the non-carriers and the APParc carriers had significantly higher levels of sAPP β than the non-carriers. There was no correlation between sAPP α or sAPPβ levels and years to expected disease onset in any of the groups. Autosomal dominant mutations leading to familial Alzheimer disease can be associated with high or low levels of sAPP α and sAPP β, depending on the specific mutation. The lower sAPPβ levels in APPswe mutation carriers are expected as the mutation destroys the neo-epitope recognized by the capturing antibody in the sAPP β assay. It is tempting to speculate that the levels of mutated sAPPβ in fact are elevated given the established effect of the APPswe mutation on BACE1-mediated APP-processing.