{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T04:24:24Z","timestamp":1781929464656,"version":"3.54.5"},"reference-count":52,"publisher":"SAGE Publications","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:p>Background: Genetic scores for late-onset Alzheimer\u2019s 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\u2019s 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-\u03b2, 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-\u03b2, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-\u03b2 and tau, long before the onset of clinical symptoms.<\/jats:p>","DOI":"10.3233\/jad-230097","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T12:17:48Z","timestamp":1689682668000},"page":"1587-1605","source":"Crossref","is-referenced-by-count":13,"title":["Effect of Pathway-Specific Polygenic Risk Scores for Alzheimer\u2019s Disease (AD) on Rate of Change in Cognitive Function and AD-Related Biomarkers Among Asymptomatic Individuals"],"prefix":"10.1177","volume":"94","author":[{"given":"Yuexuan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Vasiljevic","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetiva K.","family":"Deming","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Wisconsin Alzheimer\u2019s Institute, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Jonaitis","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer\u2019s Institute, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Koscik","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Wisconsin Alzheimer\u2019s Institute, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol A.","family":"Van Hulle","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongshi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Carboni","sequence":"additional","affiliation":[{"name":"Roche Diagnostics International Ltd, Rotkreuz, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendlyn","family":"Kollmorgen","sequence":"additional","affiliation":[{"name":"Roche Diagnostics GmbH, Penzberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Wild","sequence":"additional","affiliation":[{"name":"Roche Diagnostics GmbH, Penzberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia M.","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Geriatric Research Education and Clinical Center, Wm. 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