Plasma P-Tau217 and NfL Longitudinal Changes Across Neurodegenerative Diseases

Background and Objectives Plasma phospho-tau217 (p-tau 217) is a validated biomarker of Alzheimer disease (AD), and its longitudinal dynamics may reflect AD progression. Plasma neurofilament light chain (NfL) reflects axonal injury and neurodegeneration. Their trajectories may be modulated by concomitant proteinopathies such as α-synuclein (aSyn). We aimed to characterize longitudinal changes (36 months) in plasma p-tau217 and NfL across neurodegenerative and non-neurodegenerative cognitive disorders and to examine biomarker trajectories according to aSyn pathology status within AD. Methods In this prospective single-center cohort, participants were recruited from a memory clinic in Barcelona, Spain. Participants were eligible if they had cognitive impairment because of neurodegenerative or non-neurodegenerative conditions between 2019 and 2022 and if baseline and 3-year follow-up blood samples were available. CSF AD biomarkers measured with Lumipulse and aSyn pathology assessed using real-time quaking-induced conversion assay were determined at baseline and used for patient diagnosis. Plasma p-tau217 and NfL were measured with Lumipulse at baseline and 36 months and analyzed as study outcomes. Between-group differences at longitudinal level were assessed using linear mixed-effects models. Results A total of 223 participants were included: 92 AD-aSyn− (69.6 [5.6] years, 57.8% female), 15 AD-aSyn+ (69.1 [5.8] years, 53.3% female), 17 dementia with Lewy bodies (DLB)-AD− (70.9 [6.8] years, 23.5% female), 13 DLB-AD+ (age 72.3 [5.0] years, 30.8% female), 48 frontotemporal lobar dementia (FTD) (65.5 [8.8] years, 45.8% female), and 38 non-neurodegenerative cognitive impairment (NNCI) (65.3 [7.7] years, 35.9% female). At baseline, AD-aSyn+ and AD-aSyn− groups showed the highest plasma p-tau217, whereas DLB-AD+ showed intermediate levels and DLB-AD−, FTD, and NNCI the lowest. Over 36 months, AD-aSyn+ exhibited the steepest increase in p-tau217 (2.19 pg/mL; p < 0.001), whereas AD-aSyn− and DLB-AD+ showed smaller increases; DLB-AD−, FTD, and NNCI remained stable. For NfL, FTD and AD-aSyn+ had the highest levels at baseline and follow-up (both p < 0.001), with similar increases. AD-aSyn-, DLB-AD+, and DLB-AD− showed intermediate values with moderate increases, whereas NNCI displayed limited changes. Discussion Plasma p-tau217 changes longitudinally in AD, and its trajectory is modulated by α-synuclein pathology. Patients with AD-aSyn+ show higher levels of NfL, similar to FTD, highlighting greater neuroaxonal injury. α-synuclein positivity identifies an AD-aSyn+ subgroup with steeper increases in p-tau217 and NfL, supporting biomarker-based stratification for prognosis and trial enrichment.