P-TAU205 IS A BIOMARKER LINKED TO TAU-PET ABNORMALITY: A CROSS-SECTIONAL AND LONGITUDINAL STUDY.

Current fluid biomarkers for Alzheimer's disease (AD) track amyloid-β (Aβ) pathology more strongly than tau, even though clinical and cognitive decline relate more closely to tau. We evaluated cerebrospinal fluid (CSF) phosphorylated tau at epitope 205 (p-tau205), measured using immunoassays, as a biomarker of tau aggregation. A total of 2,069 samples from the BioFINDER-2 (n=1,364) and BioFINDER-1 (n=705) cohorts spanning the full AD continuum were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, cross-sectional p-tau205 correlated with Aβ-PET (R2=0.26), tau-PET (R2=0.29), cortical atrophy (R2=0.14) and cognition (MMSE, R2=0.14). Baseline p-tau205 predicted subsequent Aβ accumulation (R2=0.44) and tau-PET uptake (R2=0.33), and increased more steeply over time in Aβ-positive than Aβ-negative participants (β[95%CI]=0.16[0.12-0.21], p<0.001). Longitudinal p-tau205 change related to cortical thinning (R2=0.32) and cognitive decline (R2≥0.41). Incorporating Aβ42/40, p-tau217 and p-tau205 into a CSF-based staging model, the final p-tau205-positive stage showed the strongest cortical atrophy, cognitive impairment, and risk of incident dementia (HR=6.40[4.28-9.59]). These findings support CSF p-tau205 as a valuable marker for biological staging and progression monitoring in AD.