Plasma Aβ ratios in autosomal dominant Alzheimer’s disease: the influence of genotype

In-vitro studies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutations in-vivo . In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios between Presenilin1 (PSEN1) and Amyloid Precursor Protein (APP) carriers. We examined the relationship between plasma and in-vitro models of Aβ processing and, among PSEN1 carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma Aβ between APP and PSEN1 : 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 APP and PSEN1 compared to non-carriers (both p<0.001). Aβ profiles were reasonably consistent in plasma and cell lines. Within PSEN1 , sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO. In-vivo differences in Aβ processing between APP and PSEN1 provide insights into ADAD pathophysiology which can inform therapy development. ### Competing Interest Statement KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. NCF reports consultancy for Roche, Biogen and Ionis, and serving on a Data Safety Monitoring Board for Biogen. HR has undertaken consultancy for Roche.