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Increased in vivo amyloid-?42 production, exchange, and loss in presenilin mutation carriers.

ABSTRACT: Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-? (A?) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of A?42 compared to A?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? 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?42 to A?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?42 relative to A?40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of A?42 into plaques, leading to reduced recovery of A?42 in cerebrospinal fluid (CSF). Reversible exchange of A?42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that A?42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble A?42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in A?42 concentrations in the CSF.

SUBMITTER: Potter R

PROVIDER: S-EPMC3838868 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.

Potter Rachel R Patterson Bruce W BW Elbert Donald L DL Ovod Vitaliy V Kasten Tom T Sigurdson Wendy W Mawuenyega Kwasi K Blazey Tyler T Goate Alison A Chott Robert R Yarasheski Kevin E KE Holtzman David M DM Morris John C JC Benzinger Tammie L S TL Bateman Randall J RJ

Science translational medicine 20130601 189

Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 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 c ...[more]

PMID: 23761040

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Project description:BackgroundIn contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Dataset Information

Increased in vivo amyloid-?42 production, exchange, and loss in presenilin mutation carriers.

Publications

Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.

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