January 31, 2023 | An international team of neuroscientists expect to soon be handing off development of a promising new blood test for Alzheimer’s disease neurodegeneration to a U.S.-based biomarker company. The immunoassay selectively measures brain-derived tau (BD-tau) and was recently demonstrated to outperform both assessments of plasma total tau levels and measurements of neurofilament light chain concentration, a protein marker of nerve cell damage.
Current diagnostic methods can accurately detect abnormalities in plasma amyloid beta (Aβ) and the phosphorylated form of tau (p-tau), two of the three components of Alzheimer’s pathology required to confidently diagnose Alzheimer’s, according to Thomas Karikari, Ph.D., assistant professor of psychiatry at the University of Pittsburgh and a researcher in the clinical neurochemistry laboratory the University of Gothenburg (Sweden). The final puzzle piece has been the big hurdle—picking up markers of BD-tau without the potential confounding effects of free-floating tau proteins produced by cells outside the brain.
Blood levels of neurofilament light are elevated in Alzheimer’s disease, Karikari says. But the same holds true for Parkinson’s and other dementias, making it hard to distinguish Alzheimer’s disease from other neurodegenerative conditions.
In a study published in Brain (DOI: 10.1093/brain/awac407), BD-tau was shown to correlate well with Alzheimer’s neurodegeneration biomarkers in the cerebrospinal fluid (CSF), which is the standard diagnostic approach. It was also found to accurately distinguish autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases, currently accomplished with neuroimaging tests using MRI and PET scanners that are expensive and unavailable to patients in many parts of the world.
Five groups, representing over 600 patient samples, were enrolled in the study. These included a discovery cohort of 10 neurochemically defined Alzheimer’s disease participants (paired CSF and serum samples) and 10 controls selected based on their CSF biomarker profile; a neurochemical cohort of 24 neurochemically defined Alzheimer’s disease participants (serum samples only) and 36 age-matched controls; a neuropathology cohort of 52 research participants enrolled in the University of California San Diego Shiley-Marcos Alzheimer’s Disease Research Center (longitudinal annual assessments); and two memory clinic cohorts of 477 patients clinically diagnosed with frontotemporal lobar degeneration or Alzheimer’s disease as well as normal control individuals (375 donating plasma and 102 donating serum).
Levels of BD-tau in the neuropathology cohort were found to be associated with clinical severity of disease based on the buildup of amyloid plaques and tau tangles in the brain tissue at autopsy, Karikari says. Levels of amyloid and tau in the brain are known to correlate with the pace of disease progression and cognitive decline.
Existing blood-based neurodegeneration markers both have significant shortcomings. Neurofilament light is not specific to Alzheimer’s disease while total tau tests correlate poorly with CSF and recent studies suggest the tau being measured originates principally from peripheral, non-brain sources, he explains. Here, researchers addressed the challenge by generating an anti-tau antibody that selectively binds BD-tau and avoids the peripherally expressed “big tau” isoform.
The expectation is that an assay for BD-tau could eventually be combined with p-tau and plasma Aβ methods to improve the blood-based diagnosis of Alzheimer’s disease so that it better aligns with results obtained at autopsy or by using CSF or neuroimaging biomarkers, says Karikari. The biomarker could also help in differentiating Alzheimer’s from other brain-robbing conditions sharing some of the same symptoms.
The team is currently having discussions with a for-profit company and, should everything go as planned, it will bring the biomarker into clinical trials of drugs targeting an Alzheimer’s pathology, he adds.
The amyloid, tau, neurodegeneration (AT[N]) framework for diagnosing Alzheimer’s disease was established by the National Institute on Aging and the Alzheimer's Association in 2011. The first in vitro diagnostic test for early detection of the telltale amyloid plaques (Lumipulse G β-Amyloid Ratio [1-42/1-40] assay of Fujirebio Diagnostics) was approved for marketing by the U.S. Food and Drug Administration (FDA) earlier this year. Then, in December, the FDA similarly greenlighted Roche’s Elecsys p-tau181/Aβ42 assay.
Both require a lumbar puncture, which could meet more resistance from physicians than a venous puncture. CSF testing is also available primarily, if somewhat spottily, in North America, Europe, and Southern Australia—and only the major medical centers do MRI/PET imaging for ruling out other types of neurodegenerative dementias—making Alzheimer’s a “luxury disease” from a diagnostic standpoint, Karikari points out.
Blood tests would significantly improve the situation, and several for the A and T biomarkers are already wending their way to market, he adds.
Karikari was lead author on a study that published last year in Nature Reviews Neurology (DOI: 10.1038/s41582-022-00665-2) estimating that the price of such tests will eventually come down to about $50. That would translate into enormous savings for clinical trial sponsors now paying several thousand dollars for a PET scan to measure amyloid and tau levels in the brain.
Blood-based testing would also be easier and more convenient to access, says Karikari, enhancing the diversity of patients willing and able to enroll in clinical studies. The participant pool needs to reflect intended real-world users of a drug if doctors are expected to prescribe it. Even the FDA recently issued explicit guidance regarding racial and ethnic diversity in trials since many drug have different effects depending on a patient’s population group.
Blood samples for assay validation testing are available thanks to clinical trials of several drugs newly approved by the FDA for the treatment of Alzheimer’s disease, says Karikari, adding that his team is focused on those showing the most promise. The hope is that BD-tau can be used to both measure the specific level of disease and the drug’s targeted pathology.
In memory clinics in several European countries, including Sweden and the Netherlands, blood tests are being used in a patient management capacity alongside traditional CSF and neuroimaging tests, he continues. Blood samples are being taken at specified time points and will be stored for later use by the research team.
The FDA has recently streamlined its approval process for drugs treating serious illnesses such as Alzheimer’s disease when the agent is expected to help more than currently available alternatives and the outcome is a biological marker. Karikari says his team is planning biological and clinical validation studies where BD-tau will be used as a companion diagnostic for various disease targets.
He suspects that a biomarker company will take over development of the assay in less than a year. The expectation is that the test will initially be marketed in the U.S. as well as Europe, where the regulatory environment tends to be “more relaxed.”
In Sweden, for example, hospitals could start using the assay experimentally once the validation work is complete, notes Karikari. Reagents could be distributed to various countries and used in accordance with prevailing regulatory guidelines.
On the academic side, the research team is particularly interested in ensuring patient cohorts in forthcoming trials represent different populations and backgrounds, including older adults with no biological evidence of Alzheimer’s disease, patients at different stages of the disease, and individuals who might have comorbidities, he says. They have recently discovered a strong association between blood biomarkers for Alzheimer’s disease and a variety of other conditions, including elevated levels of tau among patients with end-stage renal disease (Nature Medicine, DOI: 10.1038/s41591-022-01822-2 and DOI: 10.1038/s41591-022-01875-3).
“That made sense to us because tau protein that is highly expressed in the brain is also expressed in a lot of peripheral tissues and that includes... the kidneys,” says Karikari. Future studies will need to further confirm that BD-tau isn’t capturing tau from sources outside the brain, and that the assay’s accuracy in detecting Alzheimer’s is independent of various socio-demographic, clinical, and lifestyle realities.