Predictive value of a plasma p‐tau181‐specific assay for amyloid accumulation in asymptomatic Alzheimer’s Disease

Background Plasma phosphorylated tau‐181 (p‐tau181) is one of the most reliable blood‐based biomarkers for Alzheimer’s Disease (AD), yet has been consistently quantified with assays employing an antibody cross‐reacting with p‐tau175. We investigated the ability of a novel phospho‐specific plasma p‐tau181 assay to predict longitudinal amyloid accumulation in cognitively unimpaired (CU) elderly. Methods Plasma p‐tau181 was quantified with a novel Simoa‐based assay using a p‐tau181 specific antibody (ADx252) in a prospective longitudinal cohort of 78 CU elderly (baseline age[mean] = 70 years, 47% female, 51% APOE‐ε4 carriers). Plasma sampling, amyloid‐β (Aβ)‐PET ([18F]flutemetamol or [11C]PiB) and episodic memory tests (average Buschke Selective Reminding total retention /12) were performed at baseline and Aβ‐PET was repeated on average 5 years later (SD: 2, range 1‐10 years). Longitudinal amyloid accumulation was modelled through calculation of Aβ‐PET rate of change by dividing the difference between baseline and follow‐up tracer uptake (in Centiloids) by the time interval between scans (in years). A Spearman correlation matrix between longitudinal amyloid accumulation, plasma p‐tau181, baseline amyloid load, age and baseline episodic memory was calculated. Z‐scores of all variables were entered into a hierarchical regression analysis in a stepwise manner based on correlation strength and finally sex and APOE were added. Results Baseline plasma p‐tau181 correlated with longitudinal amyloid accumulation (ρ = 0.28, Figure 1A) as well as age (ρ = 0.31, Figure 1B). A negative correlation was found between age and baseline episodic memory scores (ρ = ‐0.33), and between p‐tau181 and baseline episodic memory scores (ρ = ‐0.19), although the latter did not reach significance. Apart from plasma p‐tau181, none of the other baseline variables correlated significantly with longitudinal amyloid accumulation (Figure 2). Hence, plasma p‐tau181 was entered into the base regression model. This base model (F(1,76) = 7.78, p = 0.007) explained 27% of the variance (R2) in longitudinal amyloid accumulation. Including additional predictors like demographics, clinical data or baseline amyloid load, did not further improve the model. Conclusion Plasma p‐tau181 measured with the novel phospho‐specific Simoa assay best reflects longitudinal amyloid accumulation in asymptomatic Alzheimer’s Disease with no additional predictive value of the other baseline factors included.