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We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p\u2010tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain\u2010specific cognitive decline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Participants (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)\/low(\u2212) for each biomarker using Gaussian mixture models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Among all participants, high p\u2010tau217 alone [p\u2010tau217(+)NfL(\u2013)GFAP(\u2013)] was associated with a steeper decline in episodic\/semantic memory and processing speed compared to the all\u2010low group (\n                      <jats:italic>p<\/jats:italic>\n                      \u2264 0.02). With the addition of high GFAP [p\u2010tau217(+)NfL(\u2013)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all\u2010low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p\u2010tau217(+)NfL(+)GFAP(+)];\n                      <jats:italic>p<\/jats:italic>\n                      \u2264 0.04).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>High phosphorylated tau at threonine 217 (p\u2010tau217) alone was associated with declines in semantic\/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p\u2010tau217 and GFAP.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In cognitively unimpaired individuals, subtle domain\u2010specific cognitive declines can be detected when both core and non\u2010core Alzheimer's disease biomarkers are used.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70934","type":"journal-article","created":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T12:22:28Z","timestamp":1764505348000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Combined use of plasma p\u2010tau217, NfL, and GFAP predicts domain\u2010specific cognitive decline in cognitively unimpaired and MCI individuals"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2187-6509","authenticated-orcid":false,"given":"Chao\u2010Yi","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Neurology Massachusetts General Hospital (MGH), Harvard Medical School  Charlestown Massachusetts 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