Research ArticleAlzheimer’s Disease

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

Science Translational Medicine  12 Jun 2013:
Vol. 5, Issue 189, pp. 189ra77
DOI: 10.1126/scitranslmed.3005615

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Aβ42: A Cycle of Gain and Loss

The amyloid hypothesis of Alzheimer’s disease (AD) proposes that increased production or impaired clearance of Aβ42 peptide causes deposition of amyloid in plaques, nerve destruction, and ultimately AD dementia. Animal model studies based on human autosomal dominant mutations have shown that increasing the production of Aβ peptides, especially Aβ42, can recapitulate amyloidosis. Potter et al. have now used a stable isotope labeling kinetics (SILK) approach to measure Aβ isoform kinetics to test specific hypotheses regarding the production rates of the Aβ38, Aβ40, and Aβ42 peptides in individuals carrying autosomal dominant AD mutations and related noncarriers. The authors found an increased Aβ42 production rate in AD mutation carriers that was ~25% higher than that in noncarriers. In addition to increased production rates, the authors unexpectedly found altered Aβ42 kinetics in mutation carriers that indicated both a reversible exchange pool and increased irreversible loss. Future studies could quantify the effects of proposed disease-modifying drugs to normalize altered Aβ kinetics and provide a metric to gauge target engagement for therapeutic trials.