Blood phosphorylated tau 181 predicts early, preclinical brain amyloid deposition

Abstract

AbstractBackgroundPlasma phospho‐tau181 is a promising new biomarker for Alzheimer’s disease (AD) with greater specificity than t‐tau and greater convenience compared to cerebrospinal fluid or neuroimaging biomarkers. However, its association with regional brain cortical amyloid and tau deposition is not well characterized. We evaluated 1) the association between plasma p‐tau181 levels and regional cortical amyloid and tau deposition and 2), determinants of circulating phospho‐tau181 levels.MethodPlasma p‐tau181 levels were measured in 52 [48% women, mean age 64.4 (SD 5.5)yr] cognitively normal Framingham Heart Study Offspring cohort participants at examination cycle nine (2011‐2014) who subsequently underwent 11C‐Pittsburgh Compound‐B (PiB)‐PET and/or 18F‐Flortaucipir (FTP)‐PET scans. We related phospho‐tau181 levels to PiB‐PET (composite of frontal, lateral temporal and parietal and retrosplenial cortices [FLR], as well as individual cortical regions) and FTP‐PET (entorhinal, inferior temporal and precuneus regions). Additionally, we compared p‐tau181 with plasma neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP) in predicting brain amyloid deposition.ResultThe mean time from plasma biomarker measurement to brain‐PET was 6.8 (SD 0.6)yr. On linear regression analysis adjusted for age, sex and time to PET, log p‐tau181 was associated with increased FLR (SE, 1.24±0.30, p<0.0001), precuneus (1.35±0.30, p<0.001), superofrontal (1.10±0.31, p=0.001), superotemporal (1.24±0.30, p<0.001) and insular amyloid deposition (1.17±0.31, p<0.001). Plasma p‐tau181 was not associated with tau‐PET deposition in the entorhinal (‐0.31±0.63, p=0.63), inferotemporal (‐0.19±0.64, p=0.77) or precuneus (‐0.05±0.64, p=0.94) regions, n=21 with available tau‐PET. Log NFL (1.30±0.49, p=0.01) and GFAP (1.46±0.39, p<0.0001) showed univariate associations with FLR amyloid deposition. On multivariable analysis adjusting for age, sex, apoE4 allele, AD polygenic risk score and all three biomarkers, p‐tau181 (0.92±0.31, p=0.005) and GFAP (0.92±0.41, p=0.03), but not NFL (0.25±0.51) remained associated with FLR amyloid deposition. Total cholesterol was the only vascular risk factor associated with circulating p‐tau181 levels (‐0.004±0.001, p=0.01).ConclusionElevated plasma phospho‐tau181 is associated with preclinical cortical amyloid (but not tau) deposition in a relatively young, cognitively normal sample. Circulating levels of p‐tau181 appear to be independent of vascular risk factors, highlighting the potential of phospho‐tau181 as a robust and generalizable blood‐based biomarker for AD dementia in a community‐based setting. Additional studies replicating our findings are warranted.