Utility of an Alzheimer's Disease risk-weighted polygenic risk score for predicting rates of cognitive decline in preclinical Alzheimer's Disease: A prospective longitudinal study
Authors
Tenielle Porter, Edith Cowan UniversityFollow
Samantha C. Burnham, Edith Cowan UniversityFollow
Lidija Milicic, Edith Cowan UniversityFollow
Greg Savage
Paul Maruff
Yen Ying Lim
Qiao-Xin Li
David Ames
Colin L Masters
Stephanie Rainey-Smith, Edith Cowan UniversityFollow
Christopher C. Rowe
Olivier Salvado, Edith Cowan University
David Groth
Guiseppe Verdile, Edith Cowan UniversityFollow
Victor L. Villemagne
Simon M. Laws, Edith Cowan UniversityFollow
Document Type
Journal Article
Publication Title
Journal of Alzheimer's Disease
ISSN
1875-8908
Volume
66
Issue
3
First Page
1193
Last Page
1211
PubMed ID
30412495
Publisher
IOS Press
School
School of Medical and Health Sciences / Centre for Alzheimer's Disease Research and Care / Collaborative Genomics Group
RAS ID
27930
Abstract
BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood.
OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline.
METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC).
RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype.
CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.
DOI
10.3233/JAD-180713
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Comments
Porter, T., Burnham, S. C., Milicic, L., Savage, G., Maruff, P., Lim, Y. Y., ... & Rowe, C. C. (2018). Utility of an Alzheimer's Disease risk-weighted polygenic risk score for predicting rates of cognitive decline in preclinical Alzheimer's Disease: A prospective longitudinal study. Journal of Alzheimer's Disease, 66(3). 1193-1211.
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