Thomas F. Tropea, Patricia Aldea Stevenson, Matthew Flitter, David Meehan, Amanda Sheffield Morris, Ming Lu, Leonardo Iaccarino, Emily C. Collins, Michael E. Hodsdon, David Irwin, Meredith Spindler, Andres Deik, Nabila Dahodwala, Katheryn AQ Cousins, David A. Wolk, Leslie M. Shaw, Daniel Weintraub, Edward B. Lee, Alice Chen‐Plotkin, Mark Mintun, Andrew Siderowf
OBJECTIVE: Clinically relevant Alzheimer's disease co-pathology is common in Lewy body disorders. Plasma P-tau217 is a sensitive biomarker for amyloid and tau pathology in Alzheimer's disease. The objective was to determine if plasma P-tau217 associates with Alzheimer's disease co-pathology and cognition in Lewy body disorders. METHODS: Participants had (1) a clinicopathological diagnosis of Parkinson's disease or dementia with Lewy bodies in the pathology series, or (2) a clinical diagnosis of Parkinson's disease in the clinical series and were followed as part of the longitudinal, observational cohort study at the University of Pennsylvania between 2007 and 2024. Plasma concentration of P-tau217 was measured in previously collected samples. RESULTS: Neuropathology cases included 46 Parkinson's disease and 10 dementia with Lewy bodies, and clinical cases included 173 Parkinson's disease, and 64 controls. P-tau217 was greater in cases with (median, 0.3 [interquartile range (IQR), 0.2-0.4]) versus without (median, 0.1 [IQR, 0.1-0.2]) Alzheimer's disease co-pathology (p < 0.01) and discriminates Lewy body disorders participants with Alzheimer's disease co-pathology (area under curve, 0.84). Parkinson's disease participants with incident cognitive impairment had greater increases in serial P-tau217 than those who remained cognitively stable (group × time interaction β = -0.010, p = 0.0027). Higher baseline P-tau217 concentrations associated with longitudinal change in dementia rating scale (group × time interaction β = -4.947, p = 0.0166) and higher risk for cognitive progression (hazard ratio = 1.597, p = 0.003). INTERPRETATION: Plasma P-tau217 detects Alzheimer's disease co-pathology in Lewy body disorders and predicts cognitive decline. Future studies will evaluate associations between plasma P-tau217 and imaging and clinical outcomes, in consideration for use of amyloid-targeting therapies in Lewy body disorders. ANN NEUROL 2026;99:1428-1437.