Plasma Phosphorylated Tau181 Shows Diagnostic, Prognostic Promise for Alzheimer

Oskar Hansson, MD, PhD, professor and senior neurologist, Clinical Memory Research Unit, Lund University, and Memory Clinic, Skane University Hospital

Oskar Hansson, MD, PhD

New study results published in Nature Medicine suggest that plasma phosphorylated tau181 (P-tau181) is promising as a noninvasive biomarker for Alzheimer disease, ultimately showing both prognostic and diagnostic value for use in clinical practice and trials.

The biomarker was able to differentiate between Alzheimer dementia and non-Alzheimer neurodegenerative disease with similar accuracy to tau positron emission tomography (PET) scans and cerebrospinal fluid (CSF) P-tau181 (area under the curve [AUC], 0.94 to 0.98 for different brain regions), and detected Alzheimer neuropathology in an autopsy-confirmed cohort (n = 63).

Conducted by Oskar Hansson, MD, PhD, professor and senior neurologist, Clinical Memory Research Unit, Lund University, and Memory Clinic, Skåne University Hospital, the study included 3 cohorts. These were the aforementioned neuropathology cohort (Alzheimer, n = 16; non-Alzhiemer, n = 47), as well as 2 prospective cohorts, cohort 1 (n = 182)—which included tau imaging—and cohort 2 (n = 344)—which included longitudinal follow-up to track conversion to Alzheimer dementia up to 8 years. Cohort 1 consisted of 64 cognitively unimpaired participants (60% Aβ+), 28 Aβ+ with mild cognitive impairment (MCI), 38 Aβ+ Alzheimer dementia, and 52 patients with non-Alzheimer neurodegenerative diseases. Cohort 2 was made up of 219 cognitively unimpaired participants (42% Aβ+) and 125 patients with MCI (65% Aβ+).

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“Plasma P-tau181 is promising regarding the diagnosis and prognostication of Alzheimer, especially in facilities with limited access to CSF or PET testing,” Hansson and colleagues detailed. “The most likely clinical applications are to distinguish Alzheimer from other non-Alzheimer neurodegenerative diseases in cases with mild to moderate dementia (to ensure optimal patient management, including access to available treatments), and to predict future development of Alzheimer in cases with MCI.”

They added that in clinical trials, a pairing of plasma P-tau181 with plasma Aβ42/Aβ40 would be effective in preclinical Alzheimer.

As well, Hansson et al. pointed to a recent framework developed by the National Institute on Aging and Alzheimer's Association that suggests CSF P-tau181 can be used to indicate tau status, noting that coupled with the identified correlation with CSF P-tau181, these data imply that plasma P-tau181 can also be used to in this fashion. The data revealed higher P-tau181 was associated with increased Tau PET standardized uptake value ratio (SUVR) in Braak I—IV regions of interest for the full cohort (β, 0.71; P <.001) and in those who were Aß+ (ß, 0.69; P <.001), though this was not the case for Aß- individuals (ß, 0.11; P = .48).

The biomarker also predicted positive Tau PET scans (AUC,&thinsp;0.87 to 0.91 for different brain regions). In cohort 1, the associations between plasma and CSF levels of P-tau181 were clear (n = 172; β-coefficient [β], 0.73; P <.001), and similar results were observed in cohort 2 (n = 343; ß, 0.52; P <.001). This association was observed to be significant in Aβ+ individuals, including in the presymptomatic stage (Aβ+ cognitively unimpaired), but not in Aβ— individuals.

“Prediction of longitudinal impairment to dementia is a key question for the management of individuals with mild cognitive deficits, and for the design of clinical trials in early Alzheimer. We show that, similarly to CSF Alzheimer biomarkers, plasma P-tau181 accurately predicts the development of Alzheimer dementia in people without dementia,” the investigators wrote. “When compared directly in the same subjects, plasma P-tau181 had very similar performance to CSF P-tau181 in predicting conversion to Alzheimer dementia.”

REFERENCES

1. Janelidze S, Mattsson N, Palmqvist S, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26:379—386. doi: 10.1038/s41591-020-0755-1

2. Jack Jr CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018.