Increases in p-tau181 in blood plasma associated with progressive, longitudinal neurodegeneration

1. Increases in tau phosphorylated at threonine 181 (p-tau181) in blood plasma were associated with progressive, longitudinal neurodegeneration.

2. Findings of p-tau181 were consistent with brain regions characteristic of Alzheimer’s disease, though only among participants with elevated brain amyloid-β.

Evidence Rating Level: 2 (Good)

Alzheimer’s disease (AD) is the leading form of dementia, characterized by the brain’s accumulation of amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated tau. Converging evidence suggests that plasma phosphorylated tau at threonine 181 (p-tau181) is an AD pathology biomarker that can be easily accessed. The ability of p-tau181 to monitor disease progression, however, is less clear. This longitudinal cohort study aimed to study longitudinal p-tau181 measures for assessing the progression of degenerative processes and cognitive decline in AD compared to neurofilament light chain (NfL), a disease-nonspecific marker of neuronal injury. Data between February 2007 and June 2016 from the Alzheimer’s Disease Neuroimaging Initiative was used. Further, follow-up blooding sampling was performed for up to eight years and plasma p-tau181 measurements were performed in 2020. Participants were eligible if they had available plasma p-tau181 and NfL measurements as well as at least one FDG PET or MRI scan at the same study visit. Significant neurologic disorders other than AD, infarction, infection, and multiple lacunes resulted in exclusion. A total of 1,113 (M [SD] age = 74.0 [7.6] years, 46.1% female, 89.1% non-Hispanic White) were included in the final dataset. Within the sample, 34.0% were cognitively unimpaired (CU) and 66.0% were cognitively impaired (CImp). The CImp group included mild cognitive impairment (73.1%) and AD dementia (26.9%). Plasma p-tau181 changes over time were associated with cognitive decline (CU: r = -0.24, p<.001; CImp: r = 0.34, p<.001). Prospective decreases in glucose metabolism (CU: r = -0.05, p = 0.48); CImp: r = -0.27, p<.001) and gray matter volume (CU: r = -0.19, p<.001; CImp: r = -0.31, p<.001) were also associated with cognitive decline in AD-related brain regions. However, these associations were only evident in individuals with amyloid-β aggregation. Both plasma p-tau181 and NfL were found to be independently associated with neurodegeneration and cognitive decline in AD-specific brain regions, but NfL was also associated with other brain regions in amyloid-β-negative individuals. Approximately 25% to 45% of plasma p-tau181 outcomes on cognitive measures were mediated by the imaging-derived neurodegeneration markers, such that plasma p-tau181 may be linked to cognition independent of these markers. A major limitation to consider is the lack of racial/ethnic diversity among the sample studied, which may be related to a lack of neuroimaging data available among these groups in the national dataset. Overall, this study suggests that p-tau181 is an easily accessible biomarker for AD that may help predict and monitor progression of cognitive decline and neurodegeneration, specifically for individuals with AD.

Click to read the study in JAMA Neurology

Image: PD

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