Risk of dementia in ε4 carriers is mitigated by a polygenic risk score.

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 was not included in the PRS and was analyzed separately.

Results: The PRS and ε4 were associated with amyloid-positive ATN profiles, and ε4 additionally with isolated increased tau (A-T+N-). A high PRS and 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 are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.