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Alzheimer's Disease Biotechnology Brain and Mental Performance Diagnostics

Blood Biomarker Detects Early Alzheimer’s Disease

1 week, 1 day ago

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Posted on Nov 20, 2020, 6 p.m.

According to a study published in JAMA Neurology plasma p-tau217 may screen for preclinical Alzheimer’s disease.

The levels of the blood plasma tau marker changed during preclinical stages of AD, even before tau aggregates were seen on PET scans according to an analysis from the Swedish BIOFinder2 cohort. 

Oskar Hasson, MD, Ph.D., of Lund University and co-authors report that among the cognitively unimpaired older adults plasma tau phosphorylated at threonine 217 levels were increased in those who had abnormal amyloid-PET, but normal tau-PET in the entorhinal cortex.

"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," said Hansson.

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

Previous research from Hansson and associates have shown that p-tau217 discriminated Alzheimer’s disease from other neurodegenerative diseases with significantly higher accuracy than other established plasma and MRI biomarkers. 

 In an accompanying editorial Gil Rabinovici, MD and Elisabeth Thijssen MSC of the University of California agreed that progress in the development and validation of plasma p+tau217 and other blood-based biomarkers has created justifiable excitement but several important caveats need to be considered. Among their concerns biomarker validation has been largely performed on select cohorts with poor racial and ethnic diversity. 

"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."

In this study, the team evaluated 314 cognitively unimpaired older adults and 176 patients with mild cognitive impairment in the Swedish BioFINDER2 Study with 51.2% of the cohort being women and the mean age was 66 years old. Participants enrolled from January 2107 to October 210 at two Swedish hospitals and had plasma p-taus measurements, CSF studies, as well as amyloid and tau PET imaging.

Increases in all tau biomarkers were associated with positive amyloid PET, which is in line with previous literature. Plasma p-tau217 levels were increased in those who had abnormal amyloid-PET but normal tau-PET in the entorhinal cortex among the cognitively unimpaired adults compared to those who were normal for both tests. 

36 of the 38 participants who had discordant palms and PET tau measures showed positive plasma p=tau217 and negative entorhinal cortex tau-PET; and event-based modelling 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.

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

These findings contribute to an emerging consensus that fluid biomarkers are detecting amyloid-beta-triggered changes in tau phosphorylation and secretion according to the researchers. "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."

It was noted that the study limitations included a relatively small number of participants with longitudinal tau-PET scans, lack of longitudinal plasma p-tau217 data, and the relatively young age of the 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," the authors wrote.

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https://www.medpagetoday.com/neurology/alzheimersdisease/89572

https://jamanetwork.com/journals/jamaneurology/fullarticle/2772866

https://jamanetwork.com/journals/jamaneurology/fullarticle/2772862

https://clinicaltrials.gov/ct2/show/NCT03174938

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