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Title: 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.
Austin Authors: Porter, Tenielle;Burnham, Samantha C;Milicic, Lidija;Savage, Greg;Maruff, Paul;Lim, Yen Ying;Li, Qiao-Xin;Ames, David;Masters, Colin L ;Rainey-Smith, Stephanie R;Rowe, Christopher C ;Salvado, Olivier;Groth, David;Verdile, Giuseppe;Villemagne, Victor L ;Laws, Simon M
Affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia
School of Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
Collaborative Genomics Group, Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
Co-operative Research Centre for Mental Health,
eHealth, CSIRO Health and Biosecurity, Parkville, VIC, Australia
Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
Department of Psychology, ARC Centre of Excellence in Cognition and its Disorders, Macquarie University, NSW, Australia
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
CogState Ltd., Melbourne, VIC, Australia
Academic Unit for Psychiatry of Old Age, St. Vincent's Health, The University of Melbourne, Kew, VIC, Australia
National Ageing Research Institute, Parkville, VIC, Australia
Department of Molecular Imaging and Therapy, Centre for PET, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 8-Nov-2018
Date: 2018-11-08
Publication information: Journal of Alzheimer's disease : JAD 2018; 66(3): 1193-1211
Abstract: 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. 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. 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). 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 (βhigh) 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 βhigh CN older adults is due to a saturating effect of APOE genotype. 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
ORCID: 0000-0003-3910-2453
Journal: Journal of Alzheimer's disease : JAD
PubMed URL: 30412495
Type: Journal Article
Subjects: Alzheimer’s disease
cognitive decline
episodic memory
polygenic risk scores
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