By Lucy Piper, medwireNews reporter
medwireNews: Plasma phosphorylated (p)-tau 217 shows a greater capacity to predict beta-amyloid positron emission tomography (PET) positivity than other blood biomarkers in a clinical setting, and when combined with p-tau 231, makes a strong novel biomarker for diagnosing Alzheimer’s disease (AD), show findings from two studies presented at AD/PD 2024 in Lisbon, Portugal.
For the first study, Marco Bucci (Karolinska Institute, Sweden) and colleagues quantified p-tau 217, p-tau 181, p-tau 231, and glial fibrillary acidic protein (GFAP) in 123 patients aged a mean of 65 years who were admitted to the Clinic for Cognitive Disorders at Karolinska University Hospital.
The participants were clinically assessed and classified as having mild cognitive impairment (MCI; n=74), AD (n=25), non-AD dementia (n=15), or no dementia (n=9) and were examined for beta-amyloid positivity using PET.
Out of the four biomarkers, p-tau 217 was the most closely correlated with beta-amyloid PET levels for the whole cohort, as well as consistently across each of the diagnostic subgroups.
The p-tau 217 biomarker was also the most accurate at identifying patients in the whole cohort who were beta-amyloid positive, at 93.1%, followed by GFAP at 78.0%, p-tau 231 at 68.9%, and p-tau 181 at 67.8%.
Bucci reported that predictive accuracy increased significantly to 97.5% when p-tau 217 was included alongside all the biomarkers, including the addition of neurofilament light, amyloid-beta 40, and amyloid-beta 42. While all the biomarkers in the absence of p-tau 217, yielded a lower predictive accuracy of 85.9%, which did not differ significantly to using p-tau 217 alone.
The presenter noted that the findings were similar when biomarker prediction was compared in patients with MCI before PET.
Bucci told delegates that “p-tau 217 shows clinical potential,” with a high positive predictive value of 89%, which increased to 97% when combined with the other biomarkers. Indeed, he said that “integration between plasma biomarkers and with other clinical data are warranted,” noting that false positives and false negatives in the whole cohort decreased from 8 and 6, respectively, with p-tau 217 alone to 2 and 6 when combined with other biomarkers.
In the second study, an assay detecting tau simultaneously phosphorylated at T217 and T231 (C231D217) was found to be highly sensitive and specific for the detection of AD across the disease continuum, outperforming either biomarker alone.
Anna Lidia Wojdala (Amsterdam University Medical Center, the Netherlands) and colleagues developed and validated two multiphosphorylation assays, one for C231D217 and one that detected tau simultaneously phosphorylated at T181 and T231 (C231D181).
They measured cerebrospinal fluid (CSF) and plasma C231D217 and C231D181 alongside related reference assays that detected singleplex p-tau 217, p-tau 218, and p-tau 231 in two cohorts. A discovery cohort of 55 individuals comprising 21 patients with MCI/AD, 19 with AD dementia, and 15 cognitively healthy individuals, and a validation cohort of 118 individuals, of whom 19 had preclinical AD, 20 had MCI/AD, 16 had AD dementia, 39 had frontotemporal dementia, and 24 were mentally healthy.
In the discovery and validation cohort, both CSF and plasma C231D217 were significantly increased in the AD continuum subgroups compared with controls. By contrast, in the discovery cohort, only CSF, but not plasma, C231D181 levels were significantly increased among the AD subtypes relative to controls, “so based on these results we assumed a lack of biomarker potential for plasma p-tau 231&p-tau181, and p-tau 231&p-tau 217 [to be] a highly promising biomarker,” said Wojdala.
C231D217 also distinguished patients in the validation cohort with preclinical AD from controls with an accuracy of 91%. This compared with respective accuracies of 85% and 77% for plasma p-tau 231 and 217.
Similarly, C231D217 identified 100% of individuals with MCI/AD from controls, while plasma p-tau 231 identified 97% of individuals and plasma p-tau 217 identified 90%. The corresponding accuracies for identifying individuals with AD dementia from controls were 100% versus 92% and 91%.
Analysis of the median concentration fold change in C231D217 versus p-tau 231 and p-tau 217 supported the findings and was consistent across the various subgroups.
Wojdala concluded that “p-tau217&231 is an excellent AD biomarker in both CSF and plasma,” recognizing that validation in larger cohorts is needed, as well as longitudinal studies to investigate the pattern of multiphosphorylated tau across AD progression.
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