P-Tau181 Associated With Longitudinal Neurodegeneration in Alzheimer Disease

Alexis Moscoso, PhD

Plasma phosphorylated tau at threonine 181 (p-tau181) is an accessible and scalable marker specific to Alzheimer disease (AD) for predicting and monitoring neurodegeneration and cognitive decline, according to results from a longitudinal study.

Author Alexis Moscoso, PhD, department of psychiatry and neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, and colleagues included data on 1113 participants from the Alzheimer’s Disease Neuroimaging Initiative from February 1, 2007, to June 6, 2017, and examined the potential of longitudinal plasma p-tau181 measures on neurodegeneration and cognitive decline in AD in comparison to plasma neurofilament light chain (NfL).

Among the 1113 participants, 378 individuals (34%) were cognitively unimpaired (CU) and 735 participants (66%) were cognitively impaired (CImp). Of the CImp group, 537 (73.1%) had mild cognitive impairment, and 198 (26.9%) had AD dementia.

Moscoso and colleagues found that longitudinal changes of plasma p-tau181 were associated with cognitive decline (CU: r = –0.24; P <.001; CImp: r = 0.34; P <.001) and a prospective decrease in glucose metabolism (CU: r = –0.05; P = .48; CImp: r = –0.27; P <.001) in highly-AD characteristic brain regions (FIGURE). “The study findings suggest implications for the use of plasma biomarkers as measures to monitor AD progression in clinical practice and treatment trials,” Moscoso et al concluded.

Plasma NfL similarly pronounced associations with cognition and imaging markers of neurodegeneration, but in contrast to plasma p-tau181, these associations were not AD specific.

READ MORE: Low Amyloid-β Deposition, Dopaminergic Activity Characterize MCI With Lewy Body Dementia

Similar longitudinal changes in plasma p-tau181 were associated with gray matter volume (CU: r = –0.19; P <.001; CImp: r = –0.31; P <.001) in highly-AD characteristic brain regions. All of these associations were restricted to amyloid-ß-positive individuals.

FIGURE. Plasma p-tau181

Plasma p-tau181 was also associated with future atrophy in AD-vulnerable temporoparietal regions among CU individuals (r = –0.11; P = .03). “This finding contrasts with the associations between plasma NfL and regional progressive atrophy observed in CU individuals, which were mainly pronounced in frontal regions and did not involve the temporal lobe,” the study authors concluded.

Although plasma p-tau181 and NfL were positively associated, both plasma biomarkers were independently associated with progressive AD-typical neurodegeneration with comparable effect sizes; although, for atrophy progression in the CImp group, plasma p-tau181 had a statistically significantly stronger association than plasma NfL (βp-tau181 – βNfL = –0.13; 95% CI, –0.27 to 0.00).

Along with available plasma p-tau181 and NfL measurements, participants had at least 1 fluorine-18-labeled fluorodeoxyglucose (FDG) positron emission tomography (PET) or structural magnetic resonance imaging (MRI) scan performed. Cognition was assessed using test scores from Preclinical Alzheimer Cognitive Composite and Alzheimer Disease Assessment Scale-Cognitive Subscale with 13 tasks.

Within the CU group, none of the plasma biomarkers were significantly associated with decreasing glucose metabolism. Notably, there was a reduced sample size with available longitudinal FDG PET scans (approximately 50% of total patients).

At baseline, plasma p-tau181 levels were associated with prospective cognitive decline, both in CU (r = –0.12; P = .04) and in CImp (r = 0.35; P <.001) individuals. In contrast, plasma NfL was only associated with cognitive decline among CImp individuals (CU: r = –0.06; P = .30; CImp: r = 0.26; P <.001).

Mediation analyses found that 25% to 45% of baseline plasma p-tau181 association with cognitive decline were mediated by baseline imaging neurodegeneration markers, suggesting links between plasma p-tau181 and cognition independent of these measures.

Data from a number of cohorts published in May 2020 suggested that p-tau181 can predict both tau and amyloid-ß pathologies, differentiate AD from other disorders, and identify it across the clinical spectrum.²

The findings also showed that the blood biomarker gradually increased along the Alzheimer continuum, with the lowest concentrations observed in amyloid-ß-negative young adults and cognitively unimpaired older adults, higher concentrations shown in the amyloid β-positive cognitively unimpaired older adults and mild cognitive impairment (MCI) groups, and the highest concentrations reported in the amyloid β-positive MCI and Alzheimer disease groups (P <.001 for Alzheimer vs all other groups).

REFERENCES

1. 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. Published online January 11, 2021. doi: 10.1001/jamaneurol.2020.4986

2. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modeling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-433. doi: 10.1016/S1474-4422(20)30071-5