Abstract 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&lt;0.001) and non-carriers (p&lt;0.001); higher Aβ38:40 in APP versus PSEN1 (p&lt;0.001) and non-carriers (p&lt;0.001), while Aβ42:40 was higher in APP and PSEN1 compared to non-carriers (both p&lt;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.

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