As scientists race to develop simple blood tests that could one day act as an early warning system for Alzheimer’s disease by sounding the alarm before memory problems appear, new research shows tracking shifts in certain protein biomarkers over time is more accurate than relying on a single test result.
One study presented this month found that obesity can mask signals of the disease by diluting Alzheimer’s-linked proteins, making a single blood test less reliable. Another recently published study shows that people who worried about their memory but performed normally on routine cognitive tests — and had evidence of early Alzheimer’s in their spinal fluid — showed a steeper increase in these proteins in their blood over five years than those in the same situation without the spinal fluid evidence. Some later developed abnormal indicators linked to Alzheimer’s — despite normal initial tests, the study showed.
Taken together, the research reflects continued advancements in the technology being developed to detect Alzheimer’s, even if the tests are not yet primed for widespread diagnostic use.
“Twenty years ago, when I started medical school, we could only diagnose Alzheimer’s at autopsy,” said Cyrus A. Raji, a neuroradiologist, principal investigator in the Neuroimaging Labs Research Center at Mallinckrodt Institute of Radiology at Washington University School of Medicine and senior author of the study presented this month at the Radiological Society of North America’s annual meeting. “This has revolutionized the field.”
Accelerating detection advancements
For years, detecting the way Alzheimer’s changes the brain has meant relying on brain scans or spinal taps. During a PET scan, doctors inject a radioactive tracer that makes clumps of amyloid protein — believed to contribute to plaques associated with cognitive decline — light up on brain images. When amyloid builds up abnormally, it can trigger changes in another protein, tau, which eventually wreaks havoc on how neurons communicate and leads to memory loss. A spinal tap measures those proteins in the fluid that cushions the brain and spinal cord.
But in practice, people often don’t receive these tests until they are in the later stages of cognitive decline. The tests can be expensive and hard to get because of limited equipment, shortage of trained specialists and insurance barriers. And the number people who are diagnosed — and who likely have it but remain undiagnosed — are rising, Alzheimer’s experts say.
Which is why, in part, the promise — and boom — of blood biomarkers testing has moved quickly in the last three to five years, researchers say. The FDA recently cleared two blood tests that detect Alzheimer’s-related biomarkers, and the Alzheimer’s Association issued the first clinical guidelines for their use in specialty care settings.
The FDA-approved tests do different things, said Sheena Aurora, a practicing neurologist and vice president of medical affairs at the Alzheimer’s Association. One, she said, is a “rule-out” test meant to help primary care providers determine when amyloid buildup is not likely driving the symptoms, suggesting something besides Alzheimer’s could be the culprit. The other, she said, is a “rule-in” test intended for specialists. When it comes back positive, she said that indicates a higher likelihood of Alzheimer’s-linked proteins in the brain.
The tests “are a tool,” Aurora said, noting they to be used with other diagnostic measures — family history, cognitive screen tests and imaging — not by themselves. “They’re not for risk. They are for patients who have objective signs of mild cognitive impairment.”
These are not at-home kits but medical tests that should be ordered by a clinician with experience treating dementia who can interpret them correctly, she said calling recent research that shows blood tests indicating the disease years before symptoms show up “futuristic.”
The hope offered by blood-based tests is that with a simple blood draw the same changes in amyloid and tau proteins that light up imaging scans can be detected in the bloodstream, signaling changes in the brain and expanding access to tens of millions of people.
“Alzheimer’s disease starts 20 plus years before the earliest detectable symptoms show up,” Raji said. “If we can identify individuals who have Alzheimer’s disease before they have dementia, in other words when they’re asymptomatic, then we can be more successful at applying earlier treatments that can remove these proteins and prevent the development of dementia in the future.”
Still, clinicians and researchers stress the need for caution, saying people shouldn’t rush out seeking these tests on their own. These blood tests, which they said only have limited Medicare coverage, should be used only in specific circumstances and not as a general screening tool.
Accuracy and chronic disease complications
Still, there are practical concerns to consider as chronic conditions can threaten the reliability of blood tests results. Researchers found that kidney function affects the results, making them unreliable for about one-third of older adults with kidney problems, including those with mild conditions.
Mild kidney dysfunction appeared to affect the levels of several blood-based biomarkers for Alzheimer’s disease, said Corey Bolton, a clinical neuropsychologist and assistant professor of medicine at Vanderbilt University Medical Center who co-authored the study on kidney disease. The problem was strongest for neurofilament light chain, a common biomarker that indicates nerve damage in the brain.
“This biomarker, we found, was no longer useful with people with stage three kidney disease,” he said.
Bolton said the findings underscore a broader challenge with blood tests for Alzheimer’s. Unlike PET scans or spinal taps, which reflect changes with little outside interference, blood tests must contend with the rest of the body, where kidney disease, obesity, vascular conditions and even some medications can alter protein levels and muddy the picture.
The study, which was supported in part by the Alzheimer’s Association, only measured the effects of mild to moderate chronic kidney disease and did not include participants with the most severe form of the condition.
The Centers for Disease Control and Prevention estimates that about 34 percent of Americans over 65 have chronic kidney disease — a condition that disproportionately affects some communities of color and people living in poverty. Given how common kidney disease is, researchers say it is crucial to understand how it may confound these tests.
Colton said he has been trying to figure out work-arounds, such as comparing ratios of proteins, but said there is a need to better understand how those fixes hold up among diverse patient populations given that most biomarker validation studies are “very homogenous,” meaning most of the participants are White, college-educated, relatively healthy with solid economic footing.
“What we want is to predict the disease accurately for each person,” said Argonde C. van Harten, a neurologist at the Alzheimer Center Amsterdam at Amsterdam UMC, an academic hospitalin the Netherlands, and senior author on the JAMA study along with Calvin Trieu, a physician at the memory clinic, where he is completing his doctoral studies. “In the future, we’ll need personalized treatment early in the disease.” She added that blood-based biomarkers could provide a minimally invasive window into what’s happening biologically.
The importance of testing over time
Harten and Trieu’s study followed 298 people who felt their memory was slipping but still performed normally on cognitive tests for five years. Researchers measured Alzheimer’s-linked proteins in blood — amyloid, tau, neurofilament light chain and glial fibrillary acidic (a protein expressed primarily in cells supporting the nervous system) — every two years and conducted yearly cognitive assessments.
They found that over time, a steeper increase in these proteins, especially tau and glial fibrillary acidic, was tied to measurable drops in thinking and to progression toward mild cognitive impairment or dementia.
About 20 percent of participants who started with normal biomarker levels later developed abnormal ones, the study found.
Harten stressed that their results were group-level findings and aren’t meant to be personally predictive. She also acknowledged that their cohort, who at an average age of 62, were a young group with few chronic conditions, including limited kidney function.
Taking multiple blood tests overtime provides a fuller picture of a patient’s cognitive health as opposed to a single test, which researchers say is akin to a snapshot of a moment in time.
For example, Raji tested 407 people with the six leading commercial blood tests for biomarkers that could signal links to Alzheimer’s. Baseline results appeared to indicate that a higher body mass index was connected to a lower potential of Alzheimer’s signals on both blood and brain scans. But overtime, the study showed, participants with obesity showed dramatic increases in Alzheimer’s-linked proteins compared to non-obese peers. And the blood tests detected these changes more sensitively than brain scans, which capture only late-stage amyloid buildup.
“Because people with larger bodies have a higher body mass index, and as a result, they dilute the values,” he explained. “So, if you’re looking at just one time point, you’ll get fooled.”
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