Plasma phosphorylated-tau217 shows promise as biomarker for early Alzheimer’s disease

Researchers have detected plasma phosphorylated-tau217 in the preclinical stages of Alzheimer’s disease, indicating that this protein could be a biomarker for early disease pathology, according to findings published in JAMA Neurology.

“Increasing evidence suggests that blood [phosphorylated]-tau may be a useful diagnostic and prognostic biomarker of [Alzheimer’s disease]. Increased levels of plasma tau phosphorylated at threonine 181 (P-tau181) were initially reported in patients with [Alzheimer’s disease] dementia compared with cognitively unimpaired individuals,” the researchers wrote. “In the present study ... we examined the association between plasma [phosphorylated]-tau217 and tau-[positron emission tomography].”

The present study focused specifically on early stages of Alzheimer’s disease. The main outcomes included changes in plasma phosphorylated-tau217 (P-tau217) levels in preclinical and prodromal Alzheimer’s disease compared with changes in cerebrospinal fluid measures of P-tau217 and positron emission tomography (PET) measures.

Shorena Janelidze, PhD, an assistant researcher in the clinical memory research unit of the department of clinical sciences at Lund University in Sweden, and colleagues enrolled cognitively healthy control participants (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study in their analysis, for a total of 490 participants. Women made up slightly more than half of the study population (51.2%) and the mean age of participants was 65.9 years.

The researchers enrolled participants from two hospitals in Sweden between January 2017 and October 2019. All participants completed plasma P-tau217 assessments, as well as tau- and amyloid-beta (AB)–PET imaging. A subgroup of 111 participants also underwent two or three tau-PET scans.

Janelidze and colleagues found heightened levels of plasma P-tau217 in cognitively normal individuals who had abnormal AB PET imaging but normal tau-PET in the entorhinal cortex (AB-PET-positive/tau-PET-negative group vs. AB-PET-negative/tau-PET-negative group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs. 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Their results demonstrated that most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217-positive/tau-PET-negative: 36 [94.7%]; P-tau217-negative/tau-PET-positive: 2 [5.3%]).

Event-based modeling of cross-sectional data projected that, in cognitively normal participants and those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, which would be followed by more pervasive cortical tau-PET changes, according to the researchers.

Janelidze and colleagues also analyzed the connection to global AB load in nonlinear spine models, which showed that global and CSF P-tau217 increased at lower AB-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, –0.006 to 0.041] vs –0.001 [IQR, –0.021 to 0.020]; Mann-Whitney U, P = .02).

The findings demonstrated that plasma P-tau217 is “a promising biomarker of early [Alzheimer’s disease] that might be particularly useful for patient selection and as an outcome measure to monitor drug responses in clinical trials, including individuals with preclinical [Alzheimer’s disease],” according to Janelidze and colleagues.

“Future studies in large cohorts should investigate the dynamics of plasma P-tau217 and tau-PET changes over time in relation to [AB] positivity,” the researchers wrote. “The findings of the present study should also be validated for other tau-PET tracers.”