HQ Staff Writer
March 12, 2026: For millions of people at risk of Alzheimer’s disease, a diagnosis has historically arrived too late, after memory has already begun to slip and irreversible damage has taken hold. Researchers are working hard to find ways to spot the markers before its onset. A new study published in Nature Aging by researchers at the Scripps Research Institute have added to the ongoing research. The study shows that the shape, not just the quantity, of three specific proteins circulating in the blood can signal the disease long before severe symptoms take hold.
Shape over substance
Most existing blood tests for Alzheimer’s work by measuring how much of a particular protein, usually amyloid beta or tau, is present in the bloodstream. Current tests often measure the levels of these proteins in blood or spinal fluid, but these markers may not fully capture earlier biological changes linked to disease progression.
The Scripps team took a fundamentally different approach. Rather than counting proteins, they examined how those proteins were folded — their three-dimensional shape, and specifically how “open” or “closed” certain structural sites were. “Many neurodegenerative diseases are driven by changes in protein structure,” said senior author John Yates, a professor at Scripps Research. “The question was, are there structural changes in specific proteins that might be useful as predictive markers?”
The answer turned out to be a compelling yes.
Three standout proteins
The researchers analysed blood plasma samples from 520 individuals, including people with diagnosed Alzheimer’s, people with mild cognitive impairment, and healthy controls, and volunteer research participants at the Alzheimer’s Disease Research Centers in Kansas and California. Using mass spectrometry and machine learning, the team measured how exposed or buried specific protein sites were, then looked for patterns that tracked with disease stage.
The results revealed a consistent trend: as Alzheimer’s progressed, certain blood proteins became less structurally “open.” These structural changes provided a stronger signal for distinguishing disease stage than measuring protein levels alone.
From among hundreds of candidates, three proteins emerged as the most diagnostically powerful. C1QA is involved in immune signalling; Clusterin is linked to protein folding and the clearance of amyloid; and Apolipoprotein B helps transport fats throughout the body and supports blood vessel health. Together, by tracking the structural signatures of these three proteins, the team was able to distinguish between healthy individuals, those with mild cognitive impairment, and Alzheimer’s patients with up to 93% accuracy.
Co-author Casimir Bamberger, a senior scientist at Scripps Research, described the results plainly: “The correlation was incredible.”
The implications of a highly accurate, blood-based early warning system are enormous. Alzheimer’s disease affects an estimated 7.2 million Americans age 65 and older, according to the Alzheimer’s Association. Most are diagnosed only after significant neurological damage has already occurred, at a point when therapeutic options are limited.
“Detecting markers of Alzheimer’s early is absolutely critical to developing effective therapeutics,” said Yates. “If treatment can start before significant damage has been done, it may be possible to better preserve long-term memory.”
The study also uncovered something unexpected: the test revealed distinct structural patterns by sex, offering new insights into how Alzheimer’s disease biology may differ between males and females, a dimension conventional protein-quantity tests have been unable to capture.
Not yet a clinical test
The research has real limitations. During blood preparation, the researchers had to remove highly abundant proteins to detect rarer ones, a filtering step that might have accidentally removed some disease-linked proteins physically attached to abundant ones. The longitudinal portion of the study also tracked patients for less than a year, too short a window to confirm long-term predictive power.
Despite these constraints, the study provides a robust foundation for a new class of diagnostic tests. The team is now exploring whether the same structural profiling approach could apply to other neurodegenerative diseases, including Parkinson’s and cancer.
As Dr. Richard Hodes, director of the NIH’s National Institute on Aging, summarised the significance of the work: “This work introduces a fundamentally new, blood-based approach to detecting and staging Alzheimer’s disease. By revealing protein structural changes associated with genetic risk, symptom severity, and sex differences — features not captured by existing biomarkers — this research could enable earlier diagnosis and more effective clinical trials.”