Abstract
Introduction: Diversity in cognition among apolipoprotein E () ε4 homozygotes can range from early-onset Alzheimer's disease (AD) to a lifetime with no symptoms. Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy ε4 homozygotes aged ≥75 years (n = 213) and early-onset ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity. Results: The PRS for AD was significantly higher in ε4 homozygote AD cases compared to older cognitively healthy ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0-35.2; = .003). The difference in the same PRS between ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98-9.92; = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case-controls. Discussion: A PRS for AD contributes to modified cognitive expression of the ε4/ε4 genotype at phenotypic extremes of risk.
Keywords
Alzheimer's disease, Alzheimer's disease dementia, apolipoprotein E, dementia resilience, genetic modifiers, polygenic risk score
Document Type
Journal Article
Date of Publication
1-1-2021
Publication Title
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Publisher
Wiley
School
School of Medical and Health Sciences / Centre for Precision Health
RAS ID
36631
Funders
Funding information available in the Acknowledgements section of the PDF
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Huq, A. J., Fulton‐Howard, B., Riaz, M., Laws, S., Sebra, R., Ryan, J., ... & Lacaze, P. (2021). Polygenic score modifies risk for Alzheimer's disease in APOE ε4 homozygotes at phenotypic extremes. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 13(1), e12226. https://doi.org/10.1002/dad2.12226