Amyloid-?1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

ABSTRACT: BACKGROUND:Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic A? peptides. Amongst these, A?1-43 is more prone to aggregation and has higher toxic properties than the long-known A?1-42. However, a direct effect on A?1-43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. METHODS:N?=?1431?AD patients (n?=?280 early-onset (EO) and n?=?1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, A?1-43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with A?1-42 and A?1-40 CSF levels. The soluble sAPP? and sAPP? species were also measured for the first time in mutation carriers. RESULTS:A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF A?1-43 levels compared to controls (p?=?0.037;

SUBMITTER: Perrone F 

PROVIDER: S-EPMC7488767 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature