TY - JOUR
T1 - Risk of dementia in APOE ε4 carriers is mitigated by a polygenic risk score
AU - Ebenau, Jarith L
AU - van der Lee, Sven J
AU - Hulsman, Marc
AU - Tesi, Niccolò
AU - Jansen, Iris E
AU - Verberk, Inge M W
AU - van Leeuwenstijn, Mardou
AU - Teunissen, Charlotte E
AU - Barkhof, Frederik
AU - Prins, Niels D
AU - Scheltens, Philip
AU - Holstege, Henne
AU - van Berckel, Bart N M
AU - van der Flier, Wiesje M
N1 - © 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85124428043&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34541285
U2 - https://doi.org/10.1002/dad2.12229
DO - https://doi.org/10.1002/dad2.12229
M3 - Article
C2 - 34541285
SN - 2352-8729
VL - 13
SP - e12229
JO - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
IS - 1
M1 - e12229
ER -