Long‐term cognitive and biomarker trajectories of cognitively unimpaired individuals with different levels of plasma ptau‐217

Abstract Background Plasma ptau‐217 has demonstrated excellent performance in detecting AD pathology. However, its value for predicting long‐term cognitive decline among cognitively unimpaired (CU) individuals remains unclear. Method We analyzed data from 1044 CU older individuals (75±4yrs, 64% female) enrolled in the Vallecas Project at the CIEN Foundation (Madrid, Spain). Participants underwent annual assessments (2011‐2024), including blood sampling, clinical and neuropsychological evaluations, and MRI scanning (average follow‐up: 7.2±3.0yrs). Plasma ptau‐217 levels were measured using the LUMIPULSE platform (Fujirebio ® ). Subjects were categorized as having either “ Low ” (<0.167pg/mL), “ Intermediate ” (0.167‐0.334 pg/mL) or “ High ” (>0.334 pg/mL) baseline ptau‐217 based on a pre‐established two cut‐off strategy. Generalized additive models were used to assess trajectories of (a) cognitive performance, assessed using a modified preclinical Alzheimer's cognitive composite score (mPACC5); (b) hippocampal volume, measured on serial MRI using SPM12/CAT12; and (c) blood biomarkers of astrocytic activation (GFAP) and neurodegeneration (NfL) (Simoa ® platform; n = 506). Additionally, Cox survival analysis was performed to assess the risk of progressing to MCI or dementia. All models were adjusted for sex, baseline age, APOE4, and years of education. Result 17.6% of the participants were classified as having “Intermediate” ptau‐217 levels, while 10.4% were classified as “High”. Subjects in the “High” group had lower baseline mPACC5 scores compared to the “Low” and “Intermediate” groups (d>0.5, p <0.001). Both the “High” and “Intermediate” groups showed accelerated cognitive decline compared to the “Low” group (Δslope > ‐0.3 points/year, p <0.001; Fig‐1A), and ptau‐217 was a strong predictor of conversion to MCI (“High” vs “Low”: HR=7.7; “Intermediate” vs “Low”: HR=3.3; p <0.001; Fig‐2A) and dementia (“High” vs “Low”: HR=14.3; “Intermediate” vs “Low”: HR=4.7; p <0.001; Fig‐2B). The “High” group showed smaller baseline hippocampal volumes (Δ∼5%, p <0.004) and accelerated atrophy rates compared to the other groups (Δslope = ‐0.3%/year, p < 0.01; Fig‐1B). Finally, the “Intermediate” and “High” groups showed elevated baseline GFAP (+39%, p <0.001) and NfL (+44%, p <0.02) levels, but progression did not differ between groups ( p >0.33, Fig‐3). Conclusion Our findings support the role of plasma ptau‐217 as a valuable biomarker for the early identification of CU individuals at risk for AD. Even individuals with intermediate values face an increased long‐term risk.