Plasma p-tau181

Plasma p-tau181

Frank et al. from the Boston University School of Medicine examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer’s disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL).

Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables.

Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM.

These results support plasma p-tau181 for the detection of Alzheimer’s disease dementia and the use of blood-based biomarkers for optimal disease detection 1).

Results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer’s disease biomarker 2)

Plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below the PET threshold of amyloid-β positivity or apparent entorhinal tau deposition. 3).

The study of Karikari et al. adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment. 4)

O’Connor et al. investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single-molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from the actual onset in asymptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well as testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model, there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology. 5).


Frank B, Ally M, Brekke B, Zetterberg H, Blennow K, Sugarman MA, Ashton NJ, Karikari TK, Tripodis Y, Martin B, Palmisano JN, Steinberg EG, Simkina I, Turk KW, Budson AE, O’Connor MK, Au R, Goldstein LE, Jun GR, Kowall NW, Stein TD, McKee AC, Killiany R, Qiu WQ, Stern RA, Mez J, Alosco ML. Plasma p-tau181 shows stronger network association to Alzheimer’s disease dementia than neurofilament light and total tau. Alzheimers Dement. 2021 Dec 2. doi: 10.1002/alz.12508. Epub ahead of print. PMID: 34854549.

Therriault J, Benedet AL, Pascoal TA, Lussier FZ, Tissot C, Karikari TK, Ashton NJ, Chamoun M, Bezgin G, Mathotaarachchi S, Gauthier S, Saha-Chaudhuri P, Zetterberg H, Blennow K, Rosa-Neto P; Alzheimer’s Disease Neuroimaging Initiative. Association of plasma P-tau181 with memory decline in non-demented adults. Brain Commun. 2021 Jun 14;3(3):fcab136. doi: 10.1093/braincomms/fcab136. PMID: 34222875; PMCID: PMC8249102.

Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G, Snellman A, Schöll M, Troakes C, Hye A, Gauthier S, Vanmechelen E, Zetterberg H, Rosa-Neto P, Blennow K. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol. 2021 May;141(5):709-724. doi: 10.1007/s00401-021-02275-6. Epub 2021 Feb 14. PMID: 33585983; PMCID: PMC8043944.

Karikari TK, Benedet AL, Ashton NJ, Lantero Rodriguez J, Snellman A, Suárez- Calvet M, Saha-Chaudhuri P, Lussier F, Kvartsberg H, Rial AM, Pascoal TA, Andreasson U, Schöll M, Weiner MW, Rosa-Neto P, Trojanowski JQ, Shaw LM, Blennow K, Zetterberg H; Alzheimer’s Disease Neuroimaging Initiative. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry. 2021 Feb;26(2):429-442. doi: 10.1038/s41380-020-00923-z. Epub 2020 Oct 26. PMID: 33106600.

O’Connor A, Karikari TK, Poole T, Ashton NJ, Lantero Rodriguez J, Khatun A, Swift I, Heslegrave AJ, Abel E, Chung E, Weston PSJ, Pavisic IM, Ryan NS, Barker S, Rossor MN, Polke JM, Frost C, Mead S, Blennow K, Zetterberg H, Fox NC. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry. 2020 Jul 14. doi: 10.1038/s41380-020-0838-x. Epub ahead of print. PMID: 32665603.

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