1. Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.
- Author
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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, and Zetterberg, Henrik
- Subjects
ALZHEIMER'S disease ,LIQUID chromatography-mass spectrometry ,AMYLOID beta-protein precursor ,CEREBRAL amyloid angiopathy ,GENETIC mutation ,APOLIPOPROTEIN E ,GENOTYPES - Abstract
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 < 0.001) and non-carriers (P < 0.001); higher Aβ38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aβ42:40 was higher in both mutation groups compared to non-carriers (both P < 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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