TY - JOUR
T1 - Genetically identical twin-pair difference models support the amyloid cascade hypothesis
AU - Coomans, Emma M.
AU - Tomassen, Jori
AU - Ossenkoppele, Rik
AU - Tijms, Betty M.
AU - Lorenzini, Luigi
AU - ten Kate, Mara
AU - Collij, Lyduine E.
AU - Heeman, Fiona
AU - Rikken, Roos M.
AU - van der Landen, Sophie M.
AU - den Hollander, Marijke E.
AU - Golla, Sandeep S.
AU - Yaqub, Maqsood
AU - Windhorst, Albert D.
AU - Barkhof, Frederik
AU - Scheltens, Philip
AU - de Geus, Eco J. C.
AU - Visser, Pieter Jelle
AU - van Berckel, Bart N. M.
AU - den Braber, Anouk
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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-beta pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-beta and tau in an independent manner instead of there being a causal relationship between amyloid-beta 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-beta 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 [F-18]flutemetamol (amyloid-beta)-PET, [F-18]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-beta, 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-beta were strongly associated with within-pair differences in tau (beta = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (beta = -0.37, P = 0.03) and memory functioning (beta = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (beta = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (beta = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-beta 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-beta to tau to memory functioning (proportion mediated, 51.6%).Our results indicate that associations between amyloid-beta, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-beta 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.
AB - 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-beta pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-beta and tau in an independent manner instead of there being a causal relationship between amyloid-beta 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-beta 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 [F-18]flutemetamol (amyloid-beta)-PET, [F-18]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-beta, 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-beta were strongly associated with within-pair differences in tau (beta = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (beta = -0.37, P = 0.03) and memory functioning (beta = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (beta = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (beta = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-beta 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-beta to tau to memory functioning (proportion mediated, 51.6%).Our results indicate that associations between amyloid-beta, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-beta 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.
KW - Alzheimer's disease
KW - amyloid-beta
KW - tau
KW - neurodegeneration
KW - cognition
KW - identical twins
KW - ALZHEIMERS-DISEASE
KW - TAU DEPOSITION
KW - HUMAN BRAIN
KW - PATHOLOGY
KW - BETA
KW - ASSOCIATION
U2 - 10.1093/brain/awad077
DO - 10.1093/brain/awad077
M3 - Article
C2 - 36892415
SN - 0006-8950
VL - 146
SP - 3735
EP - 3746
JO - Brain
JF - Brain
IS - 9
M1 - awad077
ER -