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O'Connor, Antoinette; Pannee, Josef; Poole, Teresa; Arber, Charles; Portelius, Erik; Swift, Imogen J; Heslegrave, Amanda J; Abel, Emily; Willumsen, Nanet; Rice, Helen; Weston, Philip S J; Ryan, Natalie S; Polke, James M; Nicholas, Jennifer M; Mead, Simon; Wray, Selina; Chávez-Gutiérrez, Lucía; Frost, Chris; Blennow, Kaj; Zetterberg, Henrik; Fox, Nick C

Plasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype

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  • Media type: E-Article
  • Title: Plasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
  • Contributor: O'Connor, Antoinette; Pannee, Josef; Poole, Teresa; Arber, Charles; Portelius, Erik; Swift, Imogen J; Heslegrave, Amanda J; Abel, Emily; Willumsen, Nanet; Rice, Helen; Weston, Philip S J; Ryan, Natalie S; Polke, James M; Nicholas, Jennifer M; Mead, Simon; Wray, Selina; Chávez-Gutiérrez, Lucía; Frost, Chris; Blennow, Kaj; Zetterberg, Henrik; Fox, Nick C
  • imprint: Oxford University Press (OUP), 2021
  • Published in: Brain
  • Language: English
  • DOI: 10.1093/brain/awab166
  • ISSN: 0006-8950; 1460-2156
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P &amp;lt; 0.001) and non-carriers (P &amp;lt; 0.001); higher Aβ38:40 in APP versus PSEN1 (P &amp;lt; 0.001) and non-carriers (P &amp;lt; 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P &amp;lt; 0.001). Amyloid-β profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aβ42:38, Aβ42:40 and Aβ38:40 ratios and parental age at onset. In vivo differences in amyloid-β processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.</jats:p>
  • Access State: Open Access