Having just gotten your mind around the slew of new p-tau markers, are you ready for more? It's happening—yet another plasma tau marker is about to be added to the Alzheimer’s diagnostic toolbox. It's not a phosphorylated fragment but isoforms spliced together only in the brain, which track with neurodegeneration. Dubbed brain-derived tau, these distinguished both autopsy-confirmed and clinically diagnosed AD from healthy controls and from other neurodegenerative diseases. Researchers led by Thomas Karikari at the University of Gothenburg, Sweden, believe brain-derived tau could be the AD-specific blood biomarker for neurodegeneration for which scientists have been searching.

  • A new immunoassay recognizes tau isoforms only made in the brain.
  • Blood and CSF concentrations of these isoforms tightly correlate.
  • This new tau may track AD-specific neurodegeneration.

In the December 27 Brain, Karikari reported that plasma concentration of these brain-derived forms of tau (BD-tau) tracked with cerebrospinal fluid markers of amyloid plaques and of neurofibrillary tangles, with postmortem plaque and tangle load, and with cognitive test scores better than plasma total tau and neurofilament light, the currently available blood markers of neurodegeneration.

“This novel work nicely highlights the potential of blood brain-derived tau as an Alzheimer’s-specific marker of neurodegeneration,” wrote Michelle Mielke, Wake Forest University, Winston-Salem, North Carolina.

“This immunoassay fills the need for measuring changes in CNS total tau in the blood,” Nicolas Barthélemy, Washington University School of Medicine, St. Louis, told Alzforum. Researchers have been using CSF total tau as a marker of damaged neurons and neurodegeneration. Randall Bateman, also at WashU, agreed. “The findings provide an opportunity to track [brain] total (i.e., non-phosphorylated) tau levels in the blood, in addition to the known p-tau measures,” he wrote (comment below).

Researchers aspire to accurately detect the amyloid-tau-neurodegeneration trifecta of AD in the blood as an easy, cost-effective way to help with diagnosis, and to monitor disease stage and progression. The plasma Aβ42/40 ratio and a handful of plasma p-tau species already can distinguish AD from other neurodegenerative diseases (Aug 2018 conference news; Mar 2020 news; Jul 2020 conference news; Feb 2021 news).

However, no AD-specific, blood-based marker of neurodegeneration currently exists. Neither plasma total tau nor plasma NfL can tell AD apart from its related diseases, though CSF t-tau can (Mar 2021 conference news; Aug 2016 conference news; Sjögren et al., 2001). Karikari suspected that plasma t-tau fails in this regard because tau made in cells outside the brain muddies the (bloody) waters.

To develop an immunoassay that avoids the murk added by peripheral tau, first author Fernando González-Ortiz searched for an antibody that binds to the six tau isoforms expressed only within the brain. All lack exon 4a, while peripherally expressed tau retains this exon. This means that only in brain-derived tau does exon 4 splice directly to exon 5. Ergo, the researchers screened for antibodies that would recognize this exon 4-5 junction, but not the 4-4a or 4a-5 junctions found in peripheral tau (see image below).

One antibody, TauJ.5H3, fit the bill. “We believe it measures many different tau species because it should bind CNS tau regardless of phosphorylation or other post-translational modifications,” Karikari said.

Brain Tau. While peripheral tau (aka "big” tau, bottom) retains exon 4a (yellow), this exon is spliced out in the making of brain-derived tau (top). This leaves exon 4 ligated directly to exon 5 in BD-tau, creating a junction unique to all isoforms of brain-derived tau. [Courtesy of González-Ortiz et al., Brain, 2022.]

With this antibody in hand, González-Ortiz developed an immunoassay to tease apart BD-tau from peripheral tau in the blood and cerebrospinal fluid. He targeted big tau with an antibody, which he has not disclosed, against exon 4a. UGot’s Kaj Blennow, who co-authored the Karikari paper, described the unpublished results in a keynote at this year’s Clinical Trials on Alzheimer’s Disease conference held November 28 to December 2 in San Francisco. Peripheral tau is undetectable in the CSF, Blennow said, but BD-tau is present in both CSF and blood, where it can be clearly distinguished from tau made in peripheral cells. This implies, fortuitously for AD researchers, that the BD-tau seeps out of the brain into the blood, but peripheral tau does not enter the CSF.

Turning his attention back to AD diagnosis, González-Ortiz next analyzed plasma and CSF samples from 609 older adults across five cohorts: two from the Sahlgrenska University Hospital in Gothenburg, two from the memory clinic at the University of Brescia in Italy, and one from the University of California, San Diego, AD Research Center. Diagnoses were determined using CSF biomarkers in the Swedish cohorts, clinical tests in the Italian cohorts, and postmortem tissue in the American cohort. Of the participants, 122 were cognitively normal, 147 had AD, and 340 had other neurodegenerative diseases, including frontotemporal dementia, Parkinson’s disease, dementia with Lewy bodies, and progressive supranuclear palsy.

How does brain-derived tau, when measured in plasma, track with its counterpart in CSF and with other AD biomarkers? CSF and blood levels correlated closely, suggesting minimal interference from peripheral tau in the plasma assay. People with AD had about 30 pg/mL and 200 pg/mL in their blood and CSF, respectively.

Moreover, high blood concentrations of BD-tau associated with low CSF Aβ42 and high plasma p-tau181 and p-tau231, all signs of brain amyloidosis. High plasma BD-tau also correlated with high CSF total tau, a marker of neurodegeneration, with coefficients ranging from 0.65 to 0.93, depending on the assay used and cohort analyzed.

However, plasma BD-tau did not correlate with plasma total tau, as expected. “It will also be important to compare plasma brain-derived tau with plasma p-tau217,” wrote Suzanne Schindler at WashU. “Studies suggest that p-tau217 may reflect aspects of amyloid, tau, and neurodegeneration,” she noted (comment below).

Importantly for differential diagnosis, people with clinically diagnosed AD had two to 9.5 times more BD-tau in their blood than did controls. In contrast, people with other neurodegenerative diseases had no increase, or even a decrease (see image below).

This AD-specific increase translated to highly accurate diagnostic power. In one of the small Swedish cohorts, plasma BD-tau distinguished 24 biomarker-diagnosed AD cases from 36 controls with an area under the curve of 1.0, indicating perfect sensitivity and specificity. BD-tau identified clinically diagnosed AD from other neurodegenerative diseases with AUCs of 0.78 to 0.99. For comparison, plasma NfL and total tau AUCs came in at 0.54 and 0.67, respectively.

Only in Alzheimer’s. Brain-derived tau was high in the blood of people clinically diagnosed with AD, but not those with other neurodegenerative diseases (left). BD-tau distinguished AD from other dementias better than did plasma NfL (right). [Courtesy of González-Ortiz et al., Brain, 2022.]

Perhaps more surprisingly, BD-tau also predicted how severe a given AD case's neuropathology and cognitive impairment were. High plasma concentrations tracked with worse plaque and tangle load in hippocampal and cortical tissue, with low Mini-Mental State Exam scores, and with high Clinical Dementia Rating global scores in the 52 participants from the UCSD neuropathology cohort.

These results reminded Barthélemy of another tau marker, the N-terminal fragment of tau called NT1 discovered by Dominic Walsh and colleagues. Some immunoassays for total tau recognize the midsection of the protein. But measuring blood NT1 distinguished AD from controls, and even predicted future neurofibrillary tangles and cognitive decline in older adults (Dec 2018 news; Dec 2020 news).

At CTAD, Dennis Selkoe of Brigham and Women’s Hospital, Boston, reported that this was also true in people who have Down’s syndrome. They carry three copies of the amyloid precursor protein gene and are, therefore, genetically destined to develop AD (May 2021 news). Selkoe's group measured plasma NT1-tau in 297 people from the Alzheimer's Biomarkers Consortium–Down Syndrome and 85 from the University of Kentucky’s longitudinal DS study (May 2021 news). As expected, plasma NT1-tau rose with age as AD pathology worsened and cognition declined, as measured by the Dementia Questionnaire for People with Learning Disabilities.

González-Ortiz told Alzforum that data from their ongoing studies suggest that plasma BD-tau predicts cognitive decline, even at early stages of AD. “It seems to be associated with the intensity of neurodegeneration,” he said.

All told, Karikari and colleagues concluded that BD-tau is a strong candidate for an AD-specific biomarker of neurodegeneration. “It would be helpful to clarify the extent to which this new biomarker provides a similar indicator of amyloid plaque burden and amyloid-related tau pathophysiology as does plasma p-tau, or whether it also provides additional information about AD-related neurodegeneration itself,” wrote Eric Reiman, Banner Alzheimer’s Institute in Phoenix (comment below).

Henrik Zetterberg of the University of Gothenburg agreed. He noted that p-tau antibodies available thus far might also pick up peripheral tau, meaning that the plasma p-tau markers used to track neuropathology might actually be measuring tau made inside and outside the brain.

Reiman also wondered whether BD-tau correlates with FDG PET measures of glucose metabolism, or even SV2A PET measure of synapse loss, or other pathological changes in AD. Mielke wants to know this, too, wondering if blood levels of BD-tau track longitudinally with brain atrophy and different clinical stages of AD (comment below).

Karikari is currently comparing plasma and CSF BD-tau levels with structural MRI as well as amyloid and tau PET. He is also tracking how the new tau marker changes across the AD clinical spectrum. Karikari told Alzforum that plasma CSF BD-tau concentrations come in higher in more advanced stages of disease.—Chelsea Weidman Burke

Comments

  1. The finding of increased brain-derived tau in the blood plasma or serum is an important advance and helps resolve why total tau in the periphery wasn’t previously specific for Alzheimer’s disease. This study adds to the growing knowledge of blood biomarkers and the relationship of how different neurodegenerative diseases can be detected by the biomolecules that are differentially transported into the systemic circulation.

    The findings are consistent with our prior observation of increased tau production specifically in Alzheimer’s due to amyloid plaques (Sato et al., 2018). They provide an opportunity to track total, i.e. non-phosphorylated, tau levels in the blood, in addition to the already known specific p-tau measures of 181, 205, 217, and 231. This will add value to our understanding of Alzheimer’s pathophysiology. These are exciting times!

    References:

    . Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018 Mar 21;97(6):1284-1298.e7. PubMed.

  2. Karikari and colleagues demonstrated that brain-derived tau, measured in plasma, performed similarly to CSF in distinguishing AD-biomarker-positive individuals. They performed an impressive number of studies in five different cohorts to validate their assay. The correlation between CSF and plasma brain-derived tau was very high (rho=0.85), similar to the rho=0.89 correlation reported for the Wash U plasma p-tau217 assay with CSF p-tau217 in a recent paper by Janelidze (Janelidze et al., 2022). 

    It would be interesting to more clearly define what specific forms of tau “brain-derived tau” represents. The assay uses an antibody that binds an epitope that represents the junction of tau exons 4 and 5, but it seems that the assay could still be reflecting a variety of tau species with different post-translational modifications (e.g., phosphorylation). 

    The plasma biomarkers used for comparison in this paper, total tau and NfL, are known to be poor AD biomarkers. While the rationale for comparison with total tau and NfL is that these biomarkers have been thought to represent neurodegeneration (the N in the ATN framework), studies suggest that p-tau217 may reflect aspects of amyloid, tau and neurodegeneration (A, T, and N). It will be important to compare plasma brain-derived tau with plasma p-tau217, which is currently one of the most promising AD biomarkers.

    References:

    . Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease. Brain. 2022 Sep 10; PubMed.

  3. It is exciting to read about the development of this brain-derived plasma Tau assay by this wonderful research group, including the way in which they have overcome the potentially confounding contributions of peripherally derived plasma total tau measurements.

    Since the findings appear to be specific for Alzheimer’s disease, it would be helpful to clarify the extent to which this new biomarker provides an indicator of amyloid plaque burden and amyloid-related tau pathophysiology similar to plasma pTau, or whether it might also provide additional information about AD-related neurodegeneration itself, even after accounting for its contributions to amyloid plaque and tau tangle burden.

    For instance, it would be interesting to see the extent to which brain-derived plasma Tau concentrations are associated with FDG PET measurements of cerebral glucose hypometabolism, SV2A PET measurements of synaptic loss, MRI measurements of hippocampal atrophy, and postmortem measurements of synaptic or neuronal loss in brain regions that are preferentially affected by AD after controlling for plasma pTau measurements in existing cohorts. In the meantime, I’d like to congratulate the team on its latest contribution to the development of promising blood-based biomarkers of AD.

  4. This novel work nicely highlights the potential of blood BD-tau as an Alzheimer’s-specific marker of neurodegeneration. There are several blood, MRI, and CSF markers of neurodegeneration but, to date, nothing that is specific to AD pathology. As the authors highlight, there are several next steps needed to understand the utility of this new blood marker, including whether it changes longitudinally with cognitive decline and brain atrophy across the AD clinical spectrum, and exactly what it’s added value is beyond plasma p-tau measures.

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References

News Citations

  1. With Sudden Progress, Blood Aβ Rivals PET at Detecting Amyloid
  2. A Phospho-Tau Plasma Assay for Alzheimer’s?
  3. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics
  4. Earliest of Them All: Blood P-Tau231 Assay Flags Pre-Amyloid Alzheimer’s
  5. FTD Fluid Markers for Degeneration: Check. For Pathology: Not Yet.
  6. Staging of Alzheimer’s, the Second: Neurodegeneration Does Not Equal Tauopathy
  7. Could a Blood Test for Tau Diagnose Alzheimer’s Disease?
  8. Plasma NT1: This Tau Snippet Predicts Cognitive Decline in Alzheimer’s
  9. In Down's Syndrome, Amyloid Vaccine Opens Door to Trials
  10. Gearing Up for Down’s Syndrome Clinical Trials

Paper Citations

  1. . Both total and phosphorylated tau are increased in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2001 May;70(5):624-30. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration. Brain. 2022 Dec 27; PubMed.