Increased in Vivo Amyloid-β42 Production, Exchange, and Loss in Presenilin Mutation Carriers

Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-beta (Ab) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of A beta 42 compared to A beta 40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of A beta isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS A beta 42 to A beta 40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble A beta 42 relative to A beta 40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of A beta 42 into plaques, leading to reduced recovery of A beta 42 in cerebrospinal fluid (CSF). Reversible exchange of A beta 42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that A beta 42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble A beta 42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in A beta 42 concentrations in the CSF.