Blood levels are elevated before tau PET is positive

Plasma levels of tau protein phosphorylated at threonine 217 (P-tau217) were elevated before tau PET scans were positive in early Alzheimer’s disease (AD), an analysis of Swedish BioFINDER-2 data found.

In context with the timing of changes seen in other biomarkers, the result suggested promise of P-tau217 as an early biomarker of Alzheimer’s.

“Plasma levels of P-tau217 were increased in early preclinical AD, and the change preceded tau-PET positivity,” wrote Oskar Hansson, MD, PhD, of the Skane University Hospital in Malmo, Sweden, and colleagues in JAMA Neurology.

“High levels of plasma P-tau217 in people with normal tau-PET were associated with a higher future increase in tau-PET signal in the entorhinal region of interest,” Hansson and colleagues continued. “Plasma P-tau217 might be a more useful biomarker than tau-PET in the earliest stages of AD (especially given the cost and accessibility of a blood test), but this needs to be further tested in longitudinal studies.”

The analysis included two groups of participants from the prospective longitudinal BioFINDER-2 study: 314 people who were cognitively unimpaired and 176 people with mild cognitive impairment. Results for fluid measures of plasma and cerebrospinal fluid (CSF) P-tau217 and for imaging measures (Aβ-PET and tau-PET) were dichotomized.

In cognitively unimpaired participants, plasma P-tau217 levels were increased in people who had abnormal Aβ-PET but normal tau-PET in the entorhinal cortex, compared with participants who had both studies negative (Aβ-PET+/ tau-PET– group versus Aβ-PET–/ tau-PET– group: median 2.2 pg/mL vs 0.7 pg/mL).

Among participants discordant for plasma P-tau217 and tau-PET, nearly all were positive for plasma P-tau217 and negative for tau-PET (94.7%, versus P-tau217–/tau-PET+ at 5.3%).

Modeling predicted that cognitively unimpaired people and those with mild cognitive impairment would show a sequence of early plasma and CSF P-tau217 elevation, then tau-PET positivity in the entorhinal cortex, followed by more widespread cortical tau-PET findings.

Changes in entorhinal cortical tau-PET positivity were greater for people with a normal baseline tau-PET but elevated baseline plasma P-tau217, compared with people who had normal baseline plasma P-tau217.

In an accompanying editorial, Elisabeth H. Thijssen, MSc, and Gil D. Rabinovici, MD, both of the University of California San Francisco, said that study findings “contribute to an emerging consensus in the field that fluid biomarkers are detecting Aβ-triggered changes in tau phosphorylation and secretion. These changes likely precede the aggregation of hyperphosphorylated tau into paired helical filaments that form neurofibrillary tangles and bind PET ligands.”

“Future studies comparing longitudinal changes in both plasma and PET measures of tau will be needed to confirm this putative chain of pathophysiological events,” they added.

Progress in the development and validation of plasma P-tau217 and other blood-based biomarkers has generated excitement in the Alzheimer’s field, with increasing attention on the standardization and reproducibility of assays for biomarkers including plasma Aβ and tau for potential routine clinical use.

“The ’biomarker revolution’ in AD has culminated in the National Institute on Aging–Alzheimer’s Association Research Framework, which reconceptualizes AD as a biologic entity that is defined entirely by amyloid, tau, and neurodegeneration (ATN) biomarkers irrespective of clinical symptoms or functional decline,” Thijssen and Rabinovici noted.

In addition to P-tau217, P-tau181 has been considered recently. A 2020 comparison that also considered a BioFINDER-2 cohort suggested plasma P-tau217 was more accurate and “was not significantly different from key CSF- or PET-based measures.”

BioFINDER-2 enrolled participants from two Swedish hospitals from January 2017 to October 2019; the cohort had 51.2% women and a mean age of 66. The cognitively unimpaired group included 225 healthy controls and 89 participants who had subjective cognitive decline only. All participants had at least one tau-PET and Aβ-PET scan along with plasma and CSF studies; a subset with more than one study provided longitudinal imaging data. Mean time between the first and the last scans was 1.6 years.

Most cognitively unimpaired participants were negative for both Aβ and tau on imaging: 80.3% were Aβ-PET–/tau-PET–, while were 15.0% were Aβ-PET+/tau-PET–, and 4.5% were Aβ-PET+/tau-PET+.

“The levels of plasma P-tau217 were increased in Aβ-positive cases even though tau-PET did not show evidence of paired helical filament–tau aggregates in the entorhinal cortex,” the researchers noted.

Plasma P-tau217 distinguished Aβ-PET+/tau-PET– cognitively unimpaired participants from Aβ-PET–/tau-PET– cognitively unimpaired participants with an area under the receiver operating characteristic curve of 0.832 (95% CI 0.771-0.89), with 79% sensitivity and specificity.

Data from 111 participants with two or more tau-PET scans suggested the yearly rate of increase in entorhinal tau-PET signal was higher in the group with high (>2.5 pg/mL) baseline p-tau217.

Limitations include a smaller number of participants with multiple tau-PET scans. In addition, the cognitively unimpaired group was relatively young.

Broader considerations affecting routine use of a blood test for AD include sample collection and assay performance. “Nearly all the work to date has been performed in expert academic or industry laboratories,” the editorialists observed, adding that biomarker validation has been largely studied in research cohorts with poor racial and ethnic diversity.

Even so, “there are many reasons to be optimistic that reliable and scalable blood tests for AD are truly on the horizon,” they added. “It seems like only a matter of time before a panel of blood tests will be widely available to assess ATN brain changes in research and in the clinic, transforming the diagnosis and care of patients in the earliest stages of AD.”

  1. Plasma levels of tau protein phosphorylated at threonine 217 (P-tau217) were elevated before tau PET scans were positive in early Alzheimer’s disease (AD), an analysis of Swedish BioFINDER-2 data found.

  2. In context with the timing of changes seen in other biomarkers, the result suggested promise of P-tau217 as an early biomarker of Alzheimer’s.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was supported by the European Research Council, the Swedish Research Council, the Knut and AliceWallenberg Foundation, the Marianne and MarcusWallenberg Foundation, the Strategic Research Area MultiPark at Lund University, the Swedish Alzheimer’s Foundation, the Swedish Brain Foundation, the Parkinson Foundation of Sweden, the Medical Faculty at Lund University, Region Skåne, The Bundy Academy, The Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skane University Hospital Foundation, and the Swedish federal government under the ALF agreement.

Hansson reported receiving grants from the Swedish Research Council, the Knut and AliceWallenberg Foundation, Roche, and Biogen; receiving financial support from GE Healthcare outside the submitted work; receiving research support from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and Company, and AVID Radiopharmaceuticals; and receiving consultancy and speaker fees (paid to the institution) from Biogen and Roche.

Rabinovici reported receiving grants from the National Institutes of Health, the Alzheimer’s Association, the American College of Radiology, the Rainwater Charitable Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging; personal fees and grants from GE Healthcare; and personal fees from Merck, Johnson & Johnson, Genentech, and JAMA Neurology outside the submitted work. Thijssen reported no disclosures.

Cat ID: 33

Topic ID: 82,33,282,404,485,33,361,255,925