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 - Holstege, Henne
AU - More Authors, null
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.
KW - Alzheimer's disease
KW - APOE
KW - ATN classification
KW - biomarkers
KW - dementia
KW - polygenic risk score
KW - subjective cognitive decline
UR - http://www.scopus.com/inward/record.url?scp=85124428043&partnerID=8YFLogxK
U2 - 10.1002/dad2.12229
DO - 10.1002/dad2.12229
M3 - Article
AN - SCOPUS:85124428043
SN - 2352-8729
VL - 13
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
IS - 1
M1 - e12229
ER -
