乌鸦传媒

Levels of a blood-based tau marker changed during preclinical stages of Alzheimer's disease, before tau aggregates were seen on PET scans, an analysis from the Swedish BIOFinder2 cohort showed.

Among cognitively unimpaired older adults, plasma tau phosphorylated at threonine 217 (p-tau217) levels were increased in those who had abnormal amyloid-PET, but normal tau-PET, in the entorhinal cortex, an early region of neurofibrillary tangle formation, reported Oskar Hansson, MD, PhD, of Lund University in Sweden, and co-authors in .

"Our results are congruent with the idea that amyloid pathology increases phosphorylation and secretion of tau in neurons, which might be an important step in the development of widespread neurofibrillary tangle pathology in Alzheimer's disease," Hansson told 乌鸦传媒.

The findings add to the growing evidence that plasma tau, especially p-tau217, may be used one day to detect and treat Alzheimer's disease.

Blood-based markers are very accessible and cost-effective compared with PET imaging and cerebrospinal fluid (CSF) biomarkers, Hansson noted. "A blood-based biomarker like plasma p-tau217, detecting early Alzheimer's pathology, can be used to identify subjects suitable for clinical trials that evaluate disease-modifying therapies during the pre-symptomatic stages of the disease," he said.

"Such markers can also be used as pharmacodynamic markers, indicating whether a new treatment has an effect on Alzheimer's pathology in the brain," he added.

Earlier research by Hansson's group and others has also shown that p-tau217 discriminated Alzheimer's from other neurodegenerative diseases with significantly higher accuracy than established plasma and MRI biomarkers.

Progress in the development and validation of plasma p-tau217 and other blood-based biomarkers has generated justifiable excitement in the field, but several important caveats need to be considered, observed Elisabeth Thijssen, MSc, and Gil Rabinovici, MD, both of the University of California San Francisco, in an .

"Nearly all the work to date has been performed in expert academic or industry laboratories using assay platforms that are not yet broadly available for clinical use," they wrote. "Blood sample collection has been strictly standardized and requires rapid centrifugation and freezing of plasma samples, procedures that are beyond the current capabilities of most commercial clinical laboratories."

Moreover, biomarker validation has been performed largely on selected cohorts with poor racial and ethnic diversity, they added.

In their analysis, Hansson and colleagues evaluated 314 cognitively unimpaired older adults and 176 patients with mild cognitive impairment in the Swedish study. Just over half (51.2%) of the cohort were women, and mean age was 66. Participants enrolled from January 2017 to October 2019 at two Swedish hospitals and had plasma p-tau217 measurements, CSF studies, and amyloid and tau PET imaging.

Consistent with previous literature, increases in all tau biomarkers were associated with positive amyloid PET, Thijssen and Rabinovici pointed out.

In cognitively unimpaired participants, plasma p-tau217 levels were increased in people who had abnormal amyloid-PET, but normal tau-PET, in the entorhinal cortex, compared with people who were normal for both tests (2.2 pg/mL vs 0.7 pg/mL, respectively).

Nearly all (36 of 38) participants who had discordant plasma and PET tau measures showed positive plasma p-tau217 and negative entorhinal cortex tau-PET. Event-based modeling of cross-sectional data predicted that both plasma and CSF p-tau217 increased before tau-PET in the entorhinal cortex, followed by more widespread cortical tau-PET changes.

Participants with normal baseline tau-PET and high baseline plasma p-tau217 had a higher longitudinal increase in tau-PET in the entorhinal cortex compared with those with low baseline plasma p-tau217.

These findings contribute to an emerging consensus that fluid biomarkers are detecting amyloid beta-triggered changes in tau phosphorylation and secretion, Thijssen and Rabinovici said.

"These changes likely precede the aggregation of hyperphosphorylated tau into paired helical filaments that form neurofibrillary tangles and bind PET ligands," they wrote.

The positive correlation between amyloid-PET and tau-PET largely was mediated by plasma p-tau217, further supporting this model of sequential changes in amyloid beta and tau biomarkers, they added, although "studies comparing longitudinal changes in both plasma and PET measures of tau will be needed to confirm this putative chain of pathophysiological events."

Study limitations included the relatively small number of participants with longitudinal tau-PET scans, the lack of longitudinal plasma p-tau217 data, and the relatively young age of cognitively unimpaired participants. "Future studies in large cohorts should investigate the dynamics of plasma p-tau217 and tau-PET changes over time in relation to amyloid-beta positivity," Hansson and co-authors wrote.

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