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

Ebenau, Jarith L., van der Lee, Sven J., Hulsman, Marc, Tesi, Niccolò, Jansen, Iris E., Verberk, Inge M.W., van Leeuwenstijn, Mardou, Teunissen, Charlotte E. +6 more·2021·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
DOI 10.1002/dad2.12229PMC PMC8438688
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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.

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  • Individuals with subjective cognitive decline and APOEε4 carriers were more likely to advance to Alzheimer disease dementia if they had a high polygenic risk score (calculated without APOE), whereas a low polygenic risk score attenuated the APOEε4 effect size.

    “Similarly, individuals with subjective cognitive decline and APOEε4 carriers were more likely to advance to AD dementia if they had a high PRS (calculated without APOE), whereas a low PRS attenuated the APOEε4 effect size22.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [22]

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Authors
Ebenau, J. L., van der Lee, S. J., Hulsman, M., Tesi, N., Jansen, I. E., Verberk, I. M. W., van Leeuwenstijn, M., Teunissen, C. E., Barkhof, F., Prins, N. D., Scheltens, P., Holstege, H., van Berckel, B. N. M., & van der Flier, W. M.
Affiliations
  • Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands
  • Neurochemistry Laboratory Department of Clinical Chemistry Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands
  • Department of Radiology & Nuclear Medicine Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands
Venue
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Publisher
Wiley
Published
2021-01
Volume
13
Issue
1
ISSN
2352-8729
DOI
10.1002/dad2.12229
PMC
PMC8438688
Cited by
19
References
9
Language
en
Licence

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