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Genetically identic...
Genetically identical twin-pair difference models support the amyloid cascade hypothesis
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- Coomans, Emma M. (författare)
- Amsterdam UMC - Vrije Universiteit Amsterdam,Vrije Universiteit Amsterdam
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- Tomassen, Jori (författare)
- Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Ossenkoppele, Rik (författare)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,LU profilområde: Proaktivt åldrande,Lunds universitets profilområden,Clinical Memory Research,Lund University Research Groups,LU Profile Area: Proactive Ageing,Lund University Profile areas,Amsterdam UMC - Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Tijms, Betty M. (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Lorenzini, Luigi (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Ten Kate, Mara (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Collij, Lyduine E. (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Heeman, Fiona, 1992 (författare)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Sahlgrenska Academy,Vrije Universiteit Amsterdam,Amsterdam Neuroscience,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Wallenberg Centre for Molecular and Translational Medicine,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Rikken, Roos M. (författare)
- Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Van Der Landen, Sophie M. (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Den Hollander, Marijke E. (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Golla, Sandeep S.V. (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Yaqub, Maqsood (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- Windhorst, Albert D. (författare)
- Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Barkhof, Frederik (författare)
- Vrije Universiteit Amsterdam,University College London,Amsterdam Neuroscience
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- Scheltens, Philip (författare)
- Amsterdam Neuroscience,Vrije Universiteit Amsterdam
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- De Geus, Eco J.C. (författare)
- Vrije Universiteit Amsterdam
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- Visser, Pieter Jelle (författare)
- Karolinska Institute,Amsterdam Neuroscience,Vrije Universiteit Amsterdam,Maastricht University
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- Van Berckel, Bart N.M. (författare)
- Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Den Braber, Anouk (författare)
- Amsterdam Neuroscience,Sahlgrenska Academy,Vrije Universiteit Amsterdam
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(creator_code:org_t)
- 2023-03-09
- 2023
- Engelska 12 s.
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:9, s. 3735-3746
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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http://kipublication...
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https://gup.ub.gu.se...
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Abstract
Ämnesord
Stäng
- 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 < 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 < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = -0.68, P < 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Alzheimer's disease
- amyloid-β
- cognition
- identical twins
- neurodegeneration
- tau
- amyloid-beta
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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- Av författaren/redakt...
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Coomans, Emma M.
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Tomassen, Jori
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Ossenkoppele, Ri ...
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Tijms, Betty M.
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Lorenzini, Luigi
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Ten Kate, Mara
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visa fler...
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Collij, Lyduine ...
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Heeman, Fiona, 1 ...
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Rikken, Roos M.
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Van Der Landen, ...
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Den Hollander, M ...
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Golla, Sandeep S ...
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Yaqub, Maqsood
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Windhorst, Alber ...
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Barkhof, Frederi ...
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Scheltens, Phili ...
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De Geus, Eco J.C ...
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Visser, Pieter J ...
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Van Berckel, Bar ...
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Den Braber, Anou ...
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