Plasma phosphorylated tau at threonine 181 (p-tau181) could be an Alzheimer disease (AD)-specific biomarker which may effectively monitor disease progression. These findings, from a longitudinal cohort study, were published in JAMA Neurology.

The AD Neuroimaging Initiative (ADNI) database was analyzed for this study. Patients with AD who were cognitively unimpaired (CU; n=378) were compared with those who were cognitively impaired (CImp; n=735). Patients underwent magnetic resonance imaging, positron emission tomography, and were assessed for blood biomarkers.

Patients were aged mean 74.0 (standard deviation [SD], 7.6) years, 53.9% were men, and 89.1% were White. The CImp cohort included patients with mild impairment (73.1%) and AD dementia (26.9%).

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Faster longitudinal progression of hypometabolism and atrophy (r, -0.28; P <.001) and gray matter volume change (r, -0.28; P <.001) was associated, among CImp patients with higher p-tau181. Among CU patients, higher p-tau181 associated with future atrophy (r, -0.11; P =.03).

Compared with the biomarker neurofilament light chain (NfL), plasma p-tau181 was more strongly associated with atrophy progression among the CImp cohort (bp-tau181 – bNfL, -0.13; 95% CI, -0.27 to 0.00). NfL associated with cognitive decline among the CImp cohort (r, 0.26; P <.001) and p-tau181 associated among both cohorts (CU: r, -0.12; P =.04; CImp: r, 0.35; P <.001).

Neurodegeneration caused by progressive decrease of glucose metabolism and increased atrophy were associated with the CImp cohort (r, -0.27; P <.001) and with a change in gray matter volume among both the CImp (r, -0.31; P <.001) and CU (r, -0.19; P <.001) cohorts. Longitudinal changes in plasma p-tau181 associated with prospective cognitive decline (CImp: r, 0.34; P <.001; CU: r, -0.24; P <.001).

Stratified by Ab status, plasma p-tau181 was associated with AD-typical regional neurodegeneration among Ab+ CImp (r, -0.27; P <.001) and with cognitive decline among patients who were Ab+ CImp (r, 0.31; P <.001) and Ab+ CU (r, -0.30; P =.003). Plasma p-tau181 was not associated with cognitive decline among Ab- patients (CImp: r, -0.01; P =.92; CU: r, -0.14; P =.05).

This study may have been biased as some patients were assessed for blood biomarkers and by brain scans at differing time periods.

These findings indicated baseline and longitudinal plasma p-tau181 may be indicative of AD-specific progressive neurodegeneration and cognitive decline, warranting additional study.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Moscoso A, Grothe MJ, Ashton NJ, et al. Longitudinal associations of blood phosphorylated tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol. 2021;e204986. doi:10.1001/jamaneurol.2020.4986