With further study, this research may provide clinical laboratories with a new proteomic biomarker for dementia screenings that identifies risk more than 10 years before symptoms appear
Researchers at the University of Warwick in the UK and Fudan University in Shanghai, China, identified four protein biomarkers in blood that they say can predict dementia up to 15 years before diagnosis. They say these biomarkers may lead to clinical laboratory blood tests that offer alternatives to costly brain scans and lumbar punctures for diagnosis of dementia.
The scientists “used the largest cohort of blood proteomics and dementia to date,” according to a University of Warwick news release. This included taking blood from 52,645 “healthy” people without dementia who participated in the UK Biobank—a population-based study cohort, the new release noted.
“The proteomic biomarkers are [easy] to access and non-invasive, and they can substantially facilitate the application of large-scale population screening,” said neurovegetative disease specialist Jin-tai Yu, MD, PhD, a professor at Fudan University and co-author of the study, in the news release.
“The advent of proteomics offers an unprecedented opportunity to predict dementia onset,” the researchers wrote.
“This is a well-conducted study that adds to what we know about changes in blood that occur very early in diseases that cause dementia, which will be important for early diagnosis in the future,” said Tara Spires-Jones, PhD, in a post from the Science Media Center in the UK. “However,” she added, “it is important to note that these are still scientific research studies and that there are currently no blood tests available for routine use that can diagnose dementia with certainty.
“Based on this study, it does seem likely that blood tests will be developed that can predict risk for developing dementia over the next 10 years, although individuals at higher risk often have difficulty knowing how to respond,” Suzanne Schindler, MD, PhD (above), told Reuters. Schindler, an Associate Professor of Neurology at Washington University in St. Louis, was not involved in the research. Clinical laboratories may soon have a new blood test for dementia. (Photo copyright: VJDementia.)
Predicting Onset of Dementia with 90% Accuracy
The researchers analyzed 52,645 blood samples from the UK Biobank (UKBB). The samples were collected between 2006 and 2010 from healthy individuals who at that time were without dementia.
By March 2023, 1,417 of the study participants had developed Alzheimer’s disease or some other form of dementia. The researchers looked at 1,463 proteins and identified four that were present in high levels among those people:
“Individuals with higher GFAP levels were 2.32 times more likely to develop dementia,” the researchers wrote in Nature Aging. “Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis.”
When adding known risk factors such as age, sex, and genetics, the researchers said they could predict onset of dementia with 90% accuracy, according to the University of Warwick news release.
“Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention,” the researchers wrote.
The news release also noted that smaller studies had already identified some of the proteins as potential biomarkers, “but this new research was much larger and conducted over several years.”
Further Validation Needed
Amanda Heslegrave, PhD, of the UK Dementia Research Institute, University College London described the UKBB as “an excellent resource” in the Science Media Center (SMC) post. However, she noted, it’s “a highly curated biobank and may not capture all populations that we need to know the risk for. The new biomarkers identified will need further validation before being used as screening tools.”
Another expert raised additional questions about the University of Warwick/Fudan University study in the SMC post.
“These results may help researchers understand the biological systems involved in the development of dementia,” said David Curtis, MD, PhD, of the UCL Genetics Institute at University College London. “However in my view the strengths of the reported associations are not really strong enough to say that these would form a useful test for predicting who will get dementia in the future.”
Conversely, Curtis pointed to other studies suggesting that phosphorylated tau (p-tau) proteins are better candidates for developing a simple blood test.
P-tau “provides a very good indicator of whether the pathological processes leading to Alzheimer’s disease are present in the brain,” he said. “When effective treatments for Alzheimer’s disease are developed it will be very helpful indeed to have simple blood tests—such as measuring phosphorylated tau—available in order to identify who could benefit.”
At least two blood tests based on the p-tau217 variant—from ALZpath and C2N—are currently available to US clinicians as laboratory developed tests (LDT).
The UK Biobank continues to be used by researchers both in the UK and abroad because of the full sets of data on large numbers of patients over many years. There are few other sources of such data elsewhere in the world. The UK Biobank is a large-scale biomedical database and research resource. It contains de-identified genetic, lifestyle and health information, and biological samples from 500,000 UK participants.
On its website, the UK Biobank states, “It is the most comprehensive and widely-used dataset of its kind and is globally accessible to approved researchers who are undertaking health-related research that is in the public interest, whether they are from academic, commercial, government or charitable settings.”
Thus, clinical laboratory managers and pathologists can expect a continuing stream of published studies that identify biomarkers associated with different health conditions and to see where the data used in these analyses came from the UK’s biobank.
Norwegian researchers reviewed large clinical trials of six common cancer screenings, including clinical laboratory tests, but some experts question the findings
Cancer screenings are a critical tool for diagnosis and treatment. But how much do they actually extend the lives of patients? According to researchers at the University of Oslo in Norway, not by much. They recently conducted a review and meta-analysis of 18 long-term clinical trials, five of the six most commonly used types of cancer screening—including two clinical laboratory tests—and found that with few exceptions, the screenings did not significantly extend lifespans.
The 18 long-term clinical trials included in the study were randomized trials that collectively included a total of 2.1 million participants. Median follow-up periods of 10 to 15 years were used to gauge estimated lifetime gain and mortality.
“The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy,” the researchers wrote in their published paper.
The researchers noted, however, that their analysis does not suggest all screenings should be abandoned. They also acknowledged that some lives are saved by screenings.
“Without screening, these patients may have died of cancer because it would have been detected at a later, incurable stage,” the scientists wrote, MedPage Today reported. “Thus, these patients experience a gain in lifetime.”
Still, some independent experts questioned the validity of the findings.
Gastroenterologist Michael Bretthauer, MD, PhD (above), a professor at the University of Oslo in Norway led the research into cancer screenings. In their JAMA Internal Medicine paper, he and his team wrote, “The findings of this meta-analysis suggest that colorectal cancer screening with sigmoidoscopy may extend life by approximately three months; lifetime gain for other screening tests appears to be unlikely or uncertain.” How their findings might affect clinical laboratory and anatomic pathology screening for cancer remains to be seen. (Photo copyright: University of Oslo.)
Pros and Cons of Cancer Screening
The clinical trials, according to MedPage Today and Oncology Nursing News covered the following tests:
Mammography screening for breast cancer (two trials).
As reported in these trials, “colorectal cancer screening with sigmoidoscopy prolonged lifetime by 110 days, while fecal testing and mammography screening did not prolong life,” the researchers wrote. “An extension of 37 days was noted for prostate cancer screening with prostate-specific antigen testing and 107 days with lung cancer screening using computed tomography, but estimates are uncertain.”
The American Cancer Society (ACS) recommends certain types of screening tests to detect cancers and pre-cancers before they can spread, thus improving the chances for survival.
The ACS advises screenings for breast cancer, colorectal cancer, and cervical cancer regardless of whether the individual is considered high risk. Lung cancer screenings are advised for people with a history of smoking. Men who are 45 to 50 or older should discuss the pros and cons of prostate cancer screening with their healthcare providers, the ACS states.
A CNN report about the University of Oslo study noted that the benefits and drawbacks of cancer screening have long been well known to doctors.
“Some positive screening results are false positives, which can lead to unnecessary anxiety as well as additional screening that can be expensive,” CNN reported. “Tests can also give a false negative and thus a false sense of security. Sometimes too, treatment can be unnecessary, resulting in a net harm rather than a net benefit, studies show.”
In their JAMA paper, the University of Oslo researchers wrote, “The critical question is whether the benefits for the few are sufficiently large to warrant the associated harms for many. It is entirely possible that multicancer detection blood tests do save lives and warrant the attendant costs and harms. But we will never know unless we ask,” CNN reported.
Hidden Impact on Cancer Mortality
ACS Chief Scientific Officer William Dahut, MD, told CNN that screenings may have an impact on cancer mortality in ways that might not be apparent from randomized trials. He noted that there’s been a decline in deaths from cervical cancer and prostate cancer since doctors began advising routine testing.
“Cancer screening was never really designed to increase longevity,” Dahut said. “Screenings are really designed to decrease premature deaths from cancer.” For example, “if a person’s life expectancy at birth was 80, a cancer screening may prevent their premature death at 65, but it wouldn’t necessarily mean they’d live to be 90 instead of the predicted 80,” CNN reported.
Dahut told CNN that fully assessing the impact of cancer screenings on life expectancy would require a clinical trial larger than those in the new study, and one that followed patients “for a very long time.”
“From its title, one would have expected this paper to be based on analysis of individual lifetime data. However, it is not,” he wrote in a compilation of expert commentary from the UK’s Science Media Center. “The paper’s conclusions are based on arithmetic manipulation of relative rates of all-cause mortality in some of the screening trials. It is therefore difficult to give credence to the claim that screening largely does not extend expected lifetime.”
He also questioned the inclusion of one particular trial in the University of Oslo study—the Canadian National Breast Screening Study—“as there is now public domain evidence of subversion of the randomization in this trial,” he added.
Another expert, Leigh Jackson, PhD, of the University of Exeter in the UK, described the University of Oslo study as “methodologically sound with some limitations which the authors clearly state.”
But he observed that “the focus on 2.1 million individuals is slightly misleading. The study considered many different screening tests and 2.1 million was indeed the total number of included patients, however, no calculation included that many people.”
Jackson also characterized the length of follow-up as a limitation. “This may have limited the amount of data included and also not considering longer follow-up may tend to underestimate the effects of screening,” he said.
This published study—along with the range of credible criticisms offered by other scientists—demonstrates how analysis of huge volumes of data is making it possible to tease out useful new insights. Clinical laboratory managers and pathologists can expect to see other examples of researchers assembling large quantities of data across different areas of medicine. This huge pools of data will be analyzed to determine the effectiveness of many medical procedures that have been performed for years with a belief that they are helpful.
