Genetically identical twin-pair difference models support the amyloid cascade hypothesis
Authors: Coomans Emma M , Tomassen Jori , Ossenkoppele Rik , Tijms Betty M , Lorenzini Luigi , ten Kate Mara , Collij Lyduine E , Heeman Fiona , Rikken Roos M , van der Landen Sophie M , den Hollander Marijke E , Golla Sandeep S V , Yaqub Maqsood , Windhorst Albert D , Barkhof Frederik , Scheltens Philip , de Geus Eco J C , Visser Pieter Jelle , van Berckel Bart N M , den Braber Anouk 
Published: March 2023

Abstract
The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association.
We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis.
At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P &lt; 0.001), and moderately associated with within-pair differences in hippocampal volume (β = −0.37, P = 0.03) and memory functioning (β = −0.57, P &lt; 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = −0.53, P &lt; 0.001) and strongly associated with within-pair differences in memory functioning (β = −0.68, P &lt; 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%).
Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.