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

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.

• Authors: Antoinette O'Connor, Josef Pannee, Teresa Poole, Charles Arber, Erik Portelius, Imogen J Swift, Amanda J Heslegrave, Emily Abel, Nanet Willumsen, Helen Rice, Philip S J Weston, Natalie S Ryan, James M Polke, Jennifer M Nicholas, Simon Mead, Selina Wray, Lucía Chávez-Gutiérrez, Chris Frost, Kaj Blennow, Henrik Zetterberg, Nick C Fox
• Journal: Brain : a journal of neurology (Brain) Vol. 144 Issue 10 Pg. 2964-2970 (11 29 2021) ISSN: 1460-2156 [Electronic] England
• PMID: 33892504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Chemical References

• Amyloid beta-Peptides
• Biomarkers
• PSEN1 protein, human
• Presenilin-1

Topics

• Adult
• Alzheimer Disease (blood, diagnosis, genetics)
• Amyloid beta-Peptides (blood, genetics)
• Biomarkers (blood)
• Cohort Studies
• Cross-Sectional Studies
• Female
• Genotype
• Humans
• Induced Pluripotent Stem Cells (metabolism)
• Longitudinal Studies
• Male
• Middle Aged
• Presenilin-1 (blood, genetics)