Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score
Jarith L. Ebenau (Vrije Universiteit Amsterdam)
Sven J. van der Lee (Amsterdam UMC, Vrije Universiteit Amsterdam, Alzheimer Center Amsterdam)
M. Hulsman (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics, Amsterdam UMC, Alzheimer Center Amsterdam)
Niccoló Tesi (Vrije Universiteit Amsterdam, TU Delft - Pattern Recognition and Bioinformatics, Alzheimer Center Amsterdam, Amsterdam UMC)
Iris E. Jansen (Amsterdam UMC, Vrije Universiteit Amsterdam, Alzheimer Center Amsterdam)
Inge M.W. Verberk (Vrije Universiteit Amsterdam)
Mardou van Leeuwenstijn (Vrije Universiteit Amsterdam)
Charlotte E. Teunissen (Vrije Universiteit Amsterdam)
H. Holstege (Amsterdam UMC, TU Delft - Intelligent Systems, Alzheimer Center Amsterdam, Vrije Universiteit Amsterdam)
G.B. More Authors (External organisation)
More Info
expand_more
Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.
Abstract
Introduction: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia. Methods: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately. Results: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A–T+N–). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers. Discussion: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
help_outline