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

Article type: Research Article

Authors: Porter, Tenielle^{a; b} | Burnham, Samantha C.^{c; d} | Milicic, Lidija^{a; b} | Savage, Greg^e | Maruff, Paul^{f; g} | Lim, Yen Ying^f | Li, Qiao-Xin^f | Ames, David^{h; i} | Masters, Colin L.^f | Rainey-Smith, Stephanie^d | Rowe, Christopher C.^{j; k} | Salvado, Olivier^a | Groth, David^m | Verdile, Giuseppe^{d; m} | Villemagne, Victor L.^{f; j; k} | Laws, Simon M.^{a; b; m; *; n} | for the AIBL Research Groupⁿ

Affiliations: [a] 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 | [b] Co-operative Research Centre for Mental Health, http://www.mentalhealthcrc.com | [c] eHealth, CSIRO Health and Biosecurity, Parkville, VIC, Australia | [d] Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia | [e] Department of Psychology, ARC Centre of Excellence in Cognition and its Disorders, Macquarie University, NSW, Australia | [f] The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia | [g] CogState Ltd., Melbourne, VIC, Australia | [h] Academic Unit for Psychiatry of Old Age, St. Vincent’s Health, The University of Melbourne, Kew, VIC, Australia | [i] National Ageing Research Institute, Parkville, VIC, Australia | [j] Department of Molecular Imaging & Therapy, Centre for PET, Austin Health, Heidelberg, VIC, Australia | [k] Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia | [l] CSIRO Health and Biosecurity/Australian e-Health Research Centre, Herston, QLD, Australia | [m] School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia | [n] http://www.aibl.csiro.au/about/aibl-research-team

Correspondence: [*] Correspondence to: A/Prof Simon M. Laws, Collaborative Genomics Group, School of Medical and Health Sciences, Edith Cowan University. 270 Joondalup Drive, Joondalup, 6027, WA, Australia. Tel.: +61 8 6304 5128; Fax: +61 8 6304 2493; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, amyloid-β , cognitive decline, episodic memory, polygenic risk scores

DOI: 10.3233/JAD-180713

Journal: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1193-1211, 2018