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.

Autor:	Xu Y; Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA., Vasiljevic E; Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA., Deming YK; Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Institute, University of Wisconsin-Madison, Madison, WI, USA., Jonaitis EM; Wisconsin Alzheimer's Institute, University of Wisconsin-Madison, Madison, WI, USA., Koscik RL; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Institute, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA., Van Hulle CA; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA., Lu Q; Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA., Carboni M; Roche Diagnostics International Ltd, Rotkreuz, Switzerland., Kollmorgen G; Roche Diagnostics GmbH, Penzberg, Germany., Wild N; Roche Diagnostics GmbH, Penzberg, Germany., Carlsson CM; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA.; Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA., Johnson SC; Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA., Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.; UK Dementia Research Institute at UCL, London, UK.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China., Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden., Engelman CD; Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Jazyk:	angličtina
Zdroj:	Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2023; Vol. 94 (4), pp. 1587-1605.
DOI:	10.3233/JAD-230097
Abstrakt:	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.
Databáze:	MEDLINE
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