Tenielle Porter1,2, Samantha C Burnham3,4, Lidija Milicic1,2, Greg Savage5, Paul Maruff6,7, Yen Ying Lim6, Qiao-Xin Li6, David Ames8,9, Colin L Masters6, Stephanie Rainey-Smith4, Christopher C Rowe10,11, Olivier Salvado1, David Groth12, Giuseppe Verdile4,12, Victor L Villemagne6,10,11, Simon M Laws1,2,12,13. 1. 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. 2. Co-operative Research Centre for Mental Health, http://www.mentalhealthcrc.com. 3. eHealth, CSIRO Health and Biosecurity, Parkville, VIC, Australia. 4. Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia. 5. Department of Psychology, ARC Centre of Excellence in Cognition and its Disorders, Macquarie University, NSW, Australia. 6. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. 7. CogState Ltd., Melbourne, VIC, Australia. 8. Academic Unit for Psychiatry of Old Age, St. Vincent's Health, The University of Melbourne, Kew, VIC, Australia. 9. National Ageing Research Institute, Parkville, VIC, Australia. 10. Department of Molecular Imaging & Therapy, Centre for PET, Austin Health, Heidelberg, VIC, Australia. 11. Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia. 12. School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Western Australia, Australia. 13. http://www.aibl.csiro.au/about/aibl-research-team.
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.
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.
Authors: Claire E Sexton; Kaarin J Anstey; Filippo Baldacci; C J Barnum; Anna M Barron; Kaj Blennow; Henry Brodaty; Samantha Burnham; Fanny M Elahi; Jürgen Götz; Yun-Hee Jeon; Maya Koronyo-Hamaoui; Susan M Landau; Nicola T Lautenschlager; Simon M Laws; Darren M Lipnicki; Hanzhang Lu; Colin L Masters; Wendy Moyle; Akinori Nakamura; Giulio Maria Pasinetti; Naren Rao; Christopher Rowe; Perminder S Sachdev; Peter R Schofield; Einar M Sigurdsson; Kate Smith; Velandai Srikanth; Cassandra Szoeke; Malú G Tansey; Rachel Whitmer; Donna Wilcock; Tien Y Wong; Lisa J Bain; Maria C Carrillo Journal: Alzheimers Dement Date: 2021-05-31 Impact factor: 16.655
Authors: Anna Zettergren; Jodie Lord; Nicholas J Ashton; Andrea L Benedet; Thomas K Karikari; Juan Lantero Rodriguez; Anniina Snellman; Marc Suárez-Calvet; Petroula Proitsi; Henrik Zetterberg; Kaj Blennow Journal: Alzheimers Res Ther Date: 2021-01-08 Impact factor: 6.982
Authors: Shane Fernandez; Samantha C Burnham; Lidija Milicic; Greg Savage; Paul Maruff; Madeline Peretti; Hamid R Sohrabi; Yen Ying Lim; Michael Weinborn; David Ames; Colin L Masters; Ralph N Martins; Stephanie Rainey-Smith; Christopher C Rowe; Olivier Salvado; David Groth; Giuseppe Verdile; Victor L Villemagne; Tenielle Porter; Simon M Laws Journal: J Alzheimers Dis Rep Date: 2021-02-24
Authors: Jarith L Ebenau; Sven J van der Lee; Marc Hulsman; Niccolò Tesi; Iris E Jansen; Inge M W Verberk; Mardou van Leeuwenstijn; Charlotte E Teunissen; Frederik Barkhof; Niels D Prins; Philip Scheltens; Henne Holstege; Bart N M van Berckel; Wiesje M van der Flier Journal: Alzheimers Dement (Amst) Date: 2021-09-14
Authors: Natasha Krishnadas; Vincent Doré; Simon M Laws; Tenielle Porter; Fiona Lamb; Svetlana Bozinovski; Victor L Villemagne; Christopher C Rowe Journal: Alzheimers Dement (Amst) Date: 2022-08-26
Authors: Christopher Fowler; Stephanie R Rainey-Smith; Sabine Bird; Julia Bomke; Pierrick Bourgeat; Belinda M Brown; Samantha C Burnham; Ashley I Bush; Carolyn Chadunow; Steven Collins; James Doecke; Vincent Doré; Kathryn A Ellis; Lis Evered; Amir Fazlollahi; Jurgen Fripp; Samantha L Gardener; Simon Gibson; Robert Grenfell; Elise Harrison; Richard Head; Liang Jin; Adrian Kamer; Fiona Lamb; Nicola T Lautenschlager; Simon M Laws; Qiao-Xin Li; Lucy Lim; Yen Ying Lim; Andrea Louey; S Lance Macaulay; Lucy Mackintosh; Ralph N Martins; Paul Maruff; Colin L Masters; Simon McBride; Lidija Milicic; Madeline Peretti; Kelly Pertile; Tenielle Porter; Morgan Radler; Alan Rembach; Joanne Robertson; Mark Rodrigues; Christopher C Rowe; Rebecca Rumble; Olivier Salvado; Greg Savage; Brendan Silbert; Magdalene Soh; Hamid R Sohrabi; Kevin Taddei; Tania Taddei; Christine Thai; Brett Trounson; Regan Tyrrell; Michael Vacher; Shiji Varghese; Victor L Villemagne; Michael Weinborn; Michael Woodward; Ying Xia; David Ames Journal: J Alzheimers Dis Rep Date: 2021-06-03