NEW YORK – New studies by independent research teams are underlining the potential for finding cerebrospinal fluid- and/or blood-based markers for cognitive decline and other disease features found in individuals with Alzheimer's disease (AD).
In the first of the studies, published in Nature Medicine on Monday, researchers from Stanford University and other centers in the US and Europe turned to SomaScan proteomic profiling to assess cerebrospinal fluid samples from nearly 3,400 participants in half a dozen case-control cohorts with deep phenotyping data.
Those analyses highlighted 675 proteins found at higher-than-usual levels in AD patients with cognitive impairment and another 721 proteins with dialed-down levels in cases marked by cognitive impairment, the team reported.
With the help of machine learning, meanwhile, the researchers focused on ties between cognitive impairment and the ratio between two synapse proteins found in the CSF samples: the protein YWHAG, which was among those with the most pronounced CSF levels in AD cases marked by cognitive impairment, and NPTX2, an excitatory synapse regulatory protein with declining representation in the presence of cognitive impairment symptoms.
"Synapse proteins emerged as the strongest correlates of [cognitive impairment], independent of A-beta and tau," co-senior and co-corresponding author Tony Wyss-Coray, a neurology and neurological sciences researcher with Stanford University, and his colleagues wrote in the first of the studies.
After validating the relationship between cognitive features and the YWHAG:NPTX2 ratio, the researchers demonstrated that the CSF protein ratio provided insights into cognitive impairment in AD beyond those explained by levels of pTau-181 or amyloid-beta-42 in the CSF, explaining an estimated 27 percent of the person-to-person cognitive impairment variance that could not be explained by those markers.
"[O]ur findings reveal that synapse proteins in the CSF and plasma are among the strongest A-beta-independent and tau-independent correlates of CI in AD, and that from these synapse proteins emerges the CSF YWHAG:NPTX2 ratio, a sparse and robust correlate of CI," the authors reported.
In a series of follow-up analyses, the team further linked the CSF protein ratio to normal aging, though such processes appeared to occur relatively early in individuals carrying AD-related autosomal dominant mutations, turning up decades before the advent of AD symptoms.
Based on the apparent ties to cognitive impairment symptoms and progression, the investigators came up with a corresponding blood plasma signature reflecting the CSF protein that "partly recapitulated" CSF YWHAG:NPTX2 ratio when tested in 13,401 blood samples from participants enrolled through Stanford's Global Neurodegeneration Proteomics Consortium or the Knight-ADRC or Religious Order Study/Memory Aging Project.
"Although more efforts are needed to improve the plasma signature, we expect that future advances in proteomics and machine learning will lead to sparse, scalable plasma surrogates of CSF YWHAG:NPTX2 to be used broadly for patient monitoring, clinical trials, and research," the authors concluded.
In another Nature Medicine paper published on Monday, a team from Washington University, Sweden's Lund University, and elsewhere considered the potential relationships between AD severity — in that case the extent of tau protein aggregation in the brain — and blood levels of the proposed marker eMTBR-tau243, an endogenously cleaved microtubule-binding region of tau.
The work builds on a 2023 study in Nature Medicine, where members of the team uncovered an uptick in MTBR-tau243 levels in CSF samples from AD patients with particularly pronounced tau tangle aggregation in the brain. In the latest effort, the investigators characterized a blood-based version of the protein, toward the goal of establishing easily accessible biomarkers to better tailor AD treatments in the future.
"We're about to enter the era of personalized medicine for Alzheimer's disease," co-first author Kanta Horie, a neurology researcher affiliated with the Washington University School of Medicine and Eisai, said in a statement, adding that "[o]nce we have a clinically available blood test for staging, plus treatments that work at different stages of the disease, doctors will be able to optimize their treatment plans for the specific needs of each patient."
"For early stages with low tau tangles, anti-amyloid therapies could be more efficacious than in late stages," he explained. "But after the onset of dementia with high tau tangles, anti-tau therapy or one of the many other experimental approaches may be more effective."
For the latest study, the researchers used a mass spectrometry-based assay to quantify eMTBR-tau243 levels in matched CSF and blood plasma samples from more than 900 participants with low, medium, or high levels of tau pathology based on positron emission tomography binding data.
There, eMTBR-tau243 levels in blood plasma progressively increased in relation to tau PET levels, notching up in individuals with mild cognitive impairment or more severe dementia, the authors reported.
"These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials," they wrote.
Washington University has licensed the blood test assay used in the study to startup C2N Diagnostics, which is developing a test for amyloid plaques in AD based on blood levels of another version of tau, known as p-tau217.
"I believe we will use blood-based p-tau217 to determine whether an individual has Alzheimer's disease, but MTBR-tau243 will be a highly valuable complement in both clinical settings and research trials," co-senior and co-corresponding author Oskar Hansson, a neurology researcher at Lund University, said in a statement. "When both of these biomarkers are positive, the likelihood that Alzheimer's is the underlying cause of a person's cognitive symptoms increases significantly, compared to when only p-tau217 is abnormal."