Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer’s Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals

Article type: Research Article

Authors: Xu, Yuexuan^a | Vasiljevic, Eva^{a; n} | Deming, Yuetiva K.^{a; b; c} | Jonaitis, Erin M.^c | Koscik, Rebecca L.^{b; c; d} | Van Hulle, Carol A.^{b; d} | Lu, Qiongshi^e | Carboni, Margherita^f | Kollmorgen, Gwendlyn^g | Wild, Norbert^g | Carlsson, Cynthia M.^{b; d; h} | Johnson, Sterling C.^{b; d} | Zetterberg, Henrik^{i; j; k; l; m} | Blennow, Kaj^{i; j} | Engelman, Corinne D.^{a; *}

Affiliations: [a] Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [b] Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [c] Wisconsin Alzheimer’s Institute, University of Wisconsin-Madison, Madison, WI, USA | [d] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA | [e] Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA | [f] Roche Diagnostics International Ltd, Rotkreuz, Switzerland | [g] Roche Diagnostics GmbH, Penzberg, Germany | [h] Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA | [i] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden | [j] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [k] UK Dementia Research Institute at UCL, London, UK | [l] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | [m] Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China | [n] Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA

Correspondence: [*] Correspondence to: Corinne D. Engelman, MSPH, PhD, Department of Population Health Sciences, University of Wisconsin – Madison, 610 Walnut Street, 1007A WARF, Madison, WI 53726-2397, USA. Tel.: +1 608 265 5491; E-mail: [email protected].

Abstract: Background:Genetic scores for late-onset Alzheimer’s disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective:In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods:PRS and p-PRSs with and without APOE were constructed separately based on the significant SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. Results:We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion:In addition to APOE, the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms.

Keywords: Aging, Alzheimer’s disease, ApoE, biomarkers, cognition, longitudinal studies

DOI: 10.3233/JAD-230097

Journal: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1587-1605, 2023