Research could lead to new biomarkers that detect Alzheimer’s much earlier than existing tests and help scientists understand why some people with the disease do not develop dementia
Key biomarkers for detecting the progression of Alzheimer’s disease have typically been based on amyloid-beta (Aβ) plaques. But these plaques show up after the disease has well-progressed and aren’t suited to early detection of the disease.
Now, researchers at the University of Pittsburgh School of Medicine (Pitt) have developed a cerebrospinal fluid (CFS) test that detects changes in tau protein prior to the formation of neurofibrillary tangles (NFTs) that proceed Aβ plaques.
With further research, Pitt’s test could lead to new clinical laboratory biomarkers that help detect the disease earlier and with more accuracy.
“The clumping of tau protein into well-ordered structures, referred to by pathologists as neurofibrillary tangles, is a more defining event for Alzheimer’s disease as it is more strongly associated with the cognitive changes,” as compared to amyloid-beta pathology, according to a Pitt news release.
The researchers showed that their CSF biomarker test worked independent of discovery of brain amyloid deposits and “correlates with severity of cognitive decline” to enable “early-stage disease diagnosis and intervention,” reported Genetic Engineering and Biotechnology News.
“Our test identifies very early stages of tau tangle formation—up to a decade before any tau clumps can show up on a brain scan,” said Thomas Karikari, PhD (above), senior author and assistant professor of psychiatry at Pitt, in a news release. (Photo copyright: University of Pittsburgh.)
Combining Biomarkers May Lead to Better Alzheimer’s Knowledge
The new biomarkers may also work with existing markers that detect amyloid-beta pathology. This could give researchers and healthcare providers a better understanding of the early stages of Alzheimer’s in specific patients.
“Amyloid-beta is a kindling, and tau is a matchstick,” said Thomas Karikari, PhD, senior author and assistant professor of psychiatry at Pitt. Karikari previously researched amyloid-beta.
“A large percentage of people who have brain amyloid-beta deposits will never develop dementia. But once the tau tangles light up on a brain scan, it may be too late to put out the fire, and their cognitive health can quickly deteriorate. Early detection of tangle-prone tau could identify the individuals who are likely to develop Alzheimer’s-associated cognitive decline and could be helped with new generation therapies,” he added.
“P-tau-217 and p-tau-181 are fantastic biomarkers. However, in the early days after we developed these markers, we wondered why they were much more reflective of amyloid pathology than tau pathology,” Karikari told MedPage Today.
“That’s what inspired this work. We believe that methods combining, say, p-tau-217 and p-tau-262 or 356, would provide more complete information on combined early-stage amyloid and tau pathologies in Alzheimer’s disease,” he noted.
Developing the Alzheimer’s Biomarker Test
Karikari and colleagues turned to biochemistry and molecular biology to develop their new test.
Specifically, they emphasized “building blocks of NFTs including oligomers and protomers” which they called “soluble tau assemblies,” Medical News Today explained.
According to the Pitt news release, using autopsied brain tissue, the researchers found:
A core region of the tau protein where NFTs form.
111 amino acids in the region.
New “phosphorylation sites of p-tau-262 and p-tau-356 can inform the status of early-stage tau aggregation that, with an appropriate intervention, could potentially be reversed.”
In other words, p-tau-262 and p-tau-356 “could predict future NFT production, making them potential biomarkers for early disease,” Medical News Today noted.
“Together, our findings inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau, and offer a diagnostic biomarker and targeted therapeutic opportunities for Alzheimer’s disease,” the authors wrote in Nature Medicine.
More Research Planned Before Clinical Lab Use
About seven million Americans are affected by Alzheimer’s, according to the Alzheimer’s Association, which expects that number to grow to 13 million by 2050. A cure for the disease does not exist.
More research is needed before the Pitt researchers’ new CSF assay can be used by clinical laboratories. Karikari said the next step is developing blood assays for the biomarkers, MedPage Today reported.
The trade association is publicly promoting the benefits of biomarker testing and AI’s benefits to diagnostics
One of the core tenets to getting federal lawmaker support for business is to tell them what an industry does. In that vein, the American Clinical Laboratory Association (ACLA) has released a new promotion that highlights applications of companion diagnostics, rapid whole genome sequencing, drug screening, biomarker testing, and infectious disease management.
One of the end goals? To sway Congress to take action against proposed reimbursement cuts to clinical lab test rates.
The ACLA campaign, known as the “Power of Knowing,” took center stage during a panel discussion at the ACLA Annual Meeting, held Feb. 27 in Washington, DC. One objective, panelists said, is to draw attention to the profession’s role in prevention and early detection of diseases, according to report from Medtech Insight.
“The association is working hard to demonstrate to policymakers the value of clinical laboratory testing through the Power of Knowing as they make policy decisions on reimbursement and clinical laboratory infrastructure that’s necessary for robust patient access to these innovative diagnostics,” said panel moderator Elyse Oveson, according to Medtech Insight. Oveson serves as ACLA chief of advocacy operations.
In March 2024, ACLA released digital ads urging Congress to pass the Saving Access to Laboratory Services Act (SALSA), which would have prevented a 15% cut in Medicare reimbursement for approximately 800 laboratory tests.
“A sustainable reform of the Medicare payment system for clinical laboratory services is vital to protect and enhance patient care, foster innovation, and ensure the stability of clinical laboratories nationwide,” ACLA president Susan Van Meter said at the time.
“If patients don’t have their biomarkers profiled for them at diagnosis and again at progression, there’s a very real chance that they would be put on the incorrect therapy that could lead to them having real harm in their health. So, we view biomarkers as critical,” said Nikki Martin (above), senior director of precision medicine initiatives for the LUNGevity Foundation, during the 2025 ACLA Annual Meeting. (Photo copyright: LinkedIn.)
Martin told attendees that biomarker tests should be part of the standard of care in lung cancer diagnosis, Medtech Insight reported. These tests analyze blood or other patient samples to identify molecules associated with specific diseases.
“For patients with non-small cell lung cancer, biomarkers are everything,” said Martin during the panel discussion. Many patients with advanced metastatic cancer, she said, “are not receiving comprehensive biomarker testing, and if they’re not, then they’re at risk of having much worse outcomes.”
Edelmayer discussed progress in developing biomarker tests for early diagnosis of Alzheimer’s disease. “The momentum is palpable among the research community,” she said. “We’re now starting to see the shift into implementation and more types of tools and technologies being available to clinicians to help patients.”
However, Edelmayer acknowledged that progress in developing Alzheimer’s tests and treatments has been slow.
“There’s never going to be a single test to help diagnose Alzheimer’s disease,” she said. “We recognize that it’s going to be a combination approach.”
New Video Campaign
The campaign’s latest advertising is summed up in a 90-second sizzle reel in which clinical laboratory leaders discuss various ways in which the profession supports healthcare.
One theme in the video is the growing use of artificial intelligence (AI) in the profession. “AI-enabled diagnostics are tools that use machine learning to analyze vast amounts of data from patient records to genomic profiles,” said Kate Sasser, PhD, chief scientific officer of Tempus, in the video. “These systems can recognize patterns in the data that humans may not easily see and help clinicians detect diseases earlier and more accurately.”
“By harnessing these cutting-edge tools, we can move closer to a world where treatments are no longer one size fits all but are instead tailored to the unique genetic and molecular profile of each patient,” said Elias Zerhouni, MD, president and vice chairman of OPKO Health, in a recent video produced as part of the ACLA’s Power of Knowing campaign.
The campaign website includes additional videos as well as downloadable graphics that can be shared on social media.
New clinical laboratory test could replace conventional spinal tap for diagnosing neurodegenerative disease
In a proof-of-concept study, University of Pittsburgh (Pitt) scientists validated a clinical laboratory test that measures more than 100 different genetic sequences associated with Alzheimer’s disease. The Pitt researchers believe the new diagnostic platform could help clinicians “capture the multifaceted nature of Alzheimer’s pathology and streamline early disease diagnostics,” according to a news release.
Clinical laboratory blood tests that detect biomarkers such as phosphorylated tau protein (pTau) have emerged in studies as diagnostic possibilities for Alzheimer’s disease, which is traditionally diagnosed using a lumbar puncture (spinal tap) procedure.
In their paper, neuroscientist Thomas Karikari, PhD, Assistant Professor of Psychiatry at University of Pittsburgh, lead author of the study, and his research team acknowledged that progress has been made in detecting Alzheimer’s disease with blood-based biomarkers. However, they note that “two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction.”
The Pitt scientists believe the focus on so-called “classical Alzheimer’s blood biomarkers” limits exploration of neurodegenerative disease.
“Alzheimer’s disease should not be looked at through one single lens. Capturing aspects of Alzheimer’s pathology in a panel of clinically validated biomarkers would increase the likelihood of stopping the disease before any cognitive symptoms emerge,” said neuroscientist Thomas Karikari, PhD (above), Assistant Professor of Psychiatry, University of Pittsburgh, and lead author of the study in a news release. Should further studies prove Pitt’s research sound, clinical laboratories may have a replacement test for diagnosing neurodegenerative disease. (Photo copyright: University of Pittsburgh.)
On its website, Alamar Biosciences explains that the disease panel offers neurological researchers:
“Multiplexed analysis of 120 neuro-specific and inflammatory proteins from 10 µl of plasma or CSF (cerebrospinal fluid).
Detection of “critical biomarkers—including pTau-217, GFAP (glial fibrillary acidic protein), NEFL (neurofilament light polypeptide) and alpha-synuclein.”
The NULISAseq test works with “a proprietary sequential immunocomplex capture and release mechanism and the latest advances in next-generation sequencing,” according to the company.
Inside Precision Medicine noted that the Alamar Biosciences assay enabled Pitt scientists to detect:
Biomarkers (usually found in CSF) “correlating with patients’ amyloid positivity status and changes in amyloid burden over time,” and,
Biomarkers including “neuroinflammation, synaptic function, and vascular health, which had not previously been validated in blood samples.”
“The performance of the NULISA platform was independently validated against conventional assays for classic Alzheimer’s biomarkers for each sample. Biomarker profiles over two years were also compared with imaging-based measures of amyloid, tau, and neurodegeneration,” LabMedica reported.
Opportunity to Track Alzheimer’s
Karikari sees the diagnostic platform being used to track individuals’ blood biomarker changes over time.
In their Molecular Neurodegeneration paper, the Pitt researchers wrote, “These (results) were not limited to markers such as pTau217, p-Tau231, p-Tau181, and GFAP, the elevation of which have consistently shown strong associations with brain Aβ [amyloid beta] and/or tau load, but included novel protein targets that inform about the disease state of the individual in different pathological stages across the biological Alzheimer’s disease continuum.”
About seven million Americans are affected by Alzheimer’s disease, according to the Alzheimer’s Association, which estimated that figure will grow to 13 billion by 2050.
Further studies by Karikari may include larger samples and greater diversity among the people studied, Inside Precision Medicine noted.
“[Karikari’s] lab is developing a predictive model that correlates biomarker changes detected using NULISAseq with brain autopsy data and cognitive assessments collected over the course of several years. Their goal is to identify blood biomarkers that can help stage the disease and predict its progression, both for decision-making around clinical management and treatment plans,” the Pitt news release states.
The Pitt scientists have developed a multiplex test that works with 100 different genetic sequences associated with Alzheimer’s. Such advances in the understanding of the human genome are giving scientists the opportunity to combine newly identified gene sequences that have a role in specific disease states.
In turn, as further studies validate the value of these biomarkers for diagnosing disease and guiding treatment decisions, clinical laboratories will have new assays that deliver more value to referring physicians and their patients.
The NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative used a cohort study of more than 10,000 individuals with and without previous COVID-19 diagnoses and compared samples using 25 common laboratory tests in hopes a useful biomarker could be identified. They were unsuccessful.
Long COVID—or PASC—is an umbrella term for those with persistent post-COVID infection symptoms that negatively impact quality of life. Though it affects millions worldwide and has been called a major public health burden, the NIH/Langone study scientists noted one glaring problem: PASC is defined differently in the major tests they studied. This makes consistent diagnoses difficult.
The study brought to light possible roadblocks that prevented biomarker identification.
“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, MD (above), director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC at NYU Langone, in a Langone Health news release. “This definition—which may evolve over time—will serve as a critical foundation for scientific discovery and treatment design.” In the future, clinical laboratories may be tasked with finding combinations of routine and reference tests that, together, enable a more precise and earlier diagnosis of long COVID. (Photo copyright: Yale School of Medicine.)
NIH/Langone Study Details
“The study … examined 25 routinely used and standardized laboratory tests chosen based on availability across institutions, prior literature, and clinical experience. These tests were conducted prospectively in laboratories that are certified by the Clinical Laboratory Improvement Amendments (CLIA). The samples were collected from 10,094 RECOVER-Adult participants, representing a diverse cohort from all over the US,” Inside Precision Medicine reported.
However, the scientists found no clinical laboratory “value” among the 25 tests examined that “reliably indicate previous infection, PASC, or the particular cluster type of PASC,” Inside Precision Medicine noted, adding that “Although some minor differences in the results of specific laboratory tests attempted to differentiate between individuals with and without a history of infection, these findings were generally clinically meaningless.”
“In a cohort study of more than 10,000 participants with and without prior SARS-CoV-2 infection, we found no evidence that any of 25 routine clinical laboratory values provide a reliable biomarker of prior infection, PASC, or the specific type of PASC cluster. … Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC,” the study authors wrote in Annals of Internal Medicine.
In addition to a vague definition of PASC, the NIH/Langone researchers noted a few other potential problems identifying a biomarker from the research.
“Use of only selected biomarkers, choice of comparison groups, if any (people who have recovered from PASC or healthy control participants); duration of symptoms; types of symptoms or phenotypes; and patient population features, such as sex, age, race, vaccination status, comorbidities, and severity of initial infection,” could be a cause for ambiguous results, the scientists wrote.
Future Research
“Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics, proteomics, metabolomics) to identify novel biomarkers,” the study authors wrote in Annals of Internal Medicine.
“Our challenge is to discover biomarkers that can help us quickly and accurately diagnose long COVID to ensure people struggling with this disease receive the most appropriate care as soon as possible,” said David Goff, MD, PhD, director of the division of cardiovascular sciences at the NIH’s National Heart, Lung, and Blood Institute, in an NHLBI news release. “Long COVID symptoms can prevent someone from returning to work or school, and may even make everyday tasks a burden, so the ability for rapid diagnosis is key.”
“Approximately one in 20 US adults reported persisting symptoms after COVID-19 in June 2024, with 1.4% reporting significant limitations,” the NIH/Langone scientists wrote in their published study.
Astute clinical laboratory scientists will recognize this as possible future diagnostic testing. There is no shortage of need.
Discovery could lead to new treatments for cancer and tumors, but probably not to any new diagnostic assays for clinical laboratories
Researchers at the University of Texas Southwestern (UTSW) Medical Center have reported discovery of “acid walls” that appear to protect various types of cancer tumors from attack by the body’s immune system cells. Though the discovery is not directly related to a biomarker for a clinical laboratory diagnostic test, the basic research will help scientists develop ways to address the tumor’s acid wall strategy for defeating the immune system.
The UT scientists made their discovery using an internally developed imaging technique that employs nanoparticle probes to detect levels of acidity in cells. The research, they suggest, “could pave the way for new cancer treatment approaches that alter the acidic environment around tumors,” according to a UTSW press release.
“This study revealed a previously unrecognized polarized extracellular acidity that is prevalent around cancer cells,” said lead study author Jinming Gao, PhD (above), Professor in the Harold C. Simmons Comprehensive Cancer Center and head of the Gao Lab at UT Southwestern Medical Center, in a press release. Gao believes the study “will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release notes. (Photo copyright: University of Texas.)
Developing Acid Walls
As explained in the press release, scientists have long known that cancer cells are slightly more acidic than most healthy tissue. Gao and his team designed a nanoparticle known as pegsitacianine—a pH-sensitive fluorescent nanoprobe for image-guided cancer surgery—that disassembles and lights up when exposed to the acidic conditions in tumors.
However, “it was unclear why these nanoparticles fluoresced since a tumor’s acidity was thought to be too mild to trigger their activation,” the press release note.
To learn more, they used nanoparticle probes to illuminate a variety of individual cancer cells sampled from humans and mice, including lung, breast, melanoma, and glioblastoma, as well as tumor tissue. They discovered that the cancer cells secreted lactic acid—a waste product of digested glucose—at higher levels than previously known. The cells “pumped” the acid away from their malignant neighbors to form a protective “acid wall” around the tumor, the researchers noted in Nature Biomedical Engineering.
“Samples from human tumors showed that this acid wall was practically devoid of CD8+ T cells within the tumors, an immune cell type known to fight cancer,” the press release states. “When the researchers grew cancer cells and CD8+ T cells together in petri dishes that had been acidified to a 5.3 pH, the cancer cells were spared while the CD8+ T cells perished within three hours, suggesting that this severe acidity might thwart immune cell attack without harming the cancer cells.”
Gao’s team previously discovered that sodium lactate, the “conjugate base of lactic acid” as they describe it, increases the longevity of T cells and thus enhances their cancer-fighting capabilities. The researchers described the two molecules—lactate and lactic acid—as “Dr. Jekyll and Mr. Hyde,” and suggested that future therapies could seek to convert lactic acid to lactate.
“Gao noted that this discovery will lead to several new lines of research, such as studies to better understand how cancer cells polarize their acid excretion, how those cells can withstand the acidity level that kills CD8+ T cells, and how to inhibit acid excretion to allow T cells to better kill cancer cells,” the press release states.
Commercializing the Technology
Pegsitacianine was designed to aid cancer surgeons by illuminating the edges of solid metastatic tumors in real time during surgery, a 2023 UTSW Medical Center press release explains. About 24 hours prior to surgery, nanoprobes are delivered via IV. Then, the surgeon uses a near-infrared camera to visualize the cells.
UTSW has licensed pegsitacianine to OncoNano Medicine, a Dallas-area biotech startup launched to commercialize technologies from Gao Lab. Gao and his colleague Baran Sumer, MD, Professor and Chief of the Division of Head and Neck Oncology in UT Southwestern Medical Center’s Department of Otolaryngology and co-author on the study, both sit on OncoNano’s advisory board.
In January 2023, OncoNano announced that pegsitacianine had received Breakthrough Therapy Designation for Real-Time Surgical Imaging from the US Food and Drug Administration (FDA), which will fast-track the technology for development and regulatory review.
In a Phase II clinical trial published in the Annals of Surgical Oncology, the researchers tested the technology as part of cytoreductive surgery in patients with peritoneal metastases. However, a November 2023 UTSW press release noted that the technology is “tumor-agnostic and could potentially be used in other forms of cancer.” It is currently ready for Phase 3 trials, according to the OncoNano website.
More research and studies are needed to better understand this dynamic of cancer cells. Collectively, this research into cancer by different scientific teams is adding new insights into the way tumors originate and spread. At this time, these insights are not expected to lead to any new diagnostics tests that pathologists and clinical laboratories could use to detect cancer.
