The relationship between longitudinal tau-PET trajectories and fluid tau biomarkers in early Braak stages is crucial for understanding Alzheimer's disease (AD) progression and identifying predictive biomarkers for early diagnosis and intervention. This study examines how baseline plasma and cerebrospinal fluid (CSF) tau biomarkers, amyloid plaques, and cognitive performance interact with longitudinal tau-PET trajectories in cognitively unimpaired (CU) individuals.

Forty-six CU individuals from ALFA+ cohort were included, each with two [18F]RO-948 tau-PET scans (∆t=2.31±0.34 years), two T1-weighted MRIs, and baseline [18F]flutemetamol amyloid-PET (Figure 1). Baseline fluid tau biomarkers, measured using RocheNTK, RocheElecsys, Simoa, and Lilly assays, as well as memory, were also available. [18F]RO-948 uptake was measured in entorhinal (BraakI/II), limbic (BraakIII/IV), and neocortical (BraakV/VI) regions and normalized to the inferior cerebellum to render SUVR. Amyloid-PET was quantified using Centiloid. Tau-PET stage transitions from baseline to follow-up assessed using predefined positivity thresholds. Linear mixed-effects models evaluated associations between baseline biomarkers, Centiloid, memory, and tau-PET SUVR over time, adjusting for age, sex, APOE-ε4, and time intervals.

Three participants (6.52%) were positive for BraakI/II at both baseline and follow-up (Stable-Positive), two (4.34%) transitioned to positive (Progressors), while the majority (41, 89.13%) remained negative (Stable-Negative) (Figure 1). Interaction between baseline predictors and time was not statistically significant for any predictive variables (Table 2). However, higher plasma ptau181 and ptau217 levels were significantly associated with higher baseline BraakI/II SUVR, while only plasma ptau181 showed a significant association with baseline BraakIII/IV. For CSF, higher ptau217 and ptau181/Aβ42 ratio were significantly associated with higher baseline tau-PET SUVR in both BraakI/II and BraakIII/IV (Table 1 & Figure 2). Additionally, Centiloid was positively associated with tau-PET SUVR in BraakI/II but not in other regions. Lower baseline memory scores were significantly associated with higher tau-PET SUVR in BraakI/II and BraakIII/IV in baseline.

Our findings support the potential of plasma and CSF tau biomarkers as early indicators of Alzheimer's pathology in cognitively unimpaired individuals. The negative association between memory and tau-PET SUVR suggests subtle cognitive differences may reflect underlying tau accumulation. However, no significant longitudinal effects were observed, likely due to the limited sample size or short follow-up.