Experts think that the biological beginnings of Alzheimer's disease might start showing up a long time before symptoms such as memory loss start appearing – perhaps even decades earlier in some cases.
Researchers are therefore searching for potential indicators or biomarkers of this underlying activity to act as early warning signs. It would mean treatment and support could be started earlier, as well as giving us more opportunities to study how the disease develops over time.
In a new study in Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, researchers from the University of Miami Miller School of Medicine analyzed four different biomarkers and their relationship to cognitive decline.
The study involved 1,170 participants with an average age of 73, who were given cognitive tests in 2016 and again in 2022. Blood tests were run only once, in 2016.
Several interesting links showed up in the data, most notably that higher levels of the Alzheimer's-related protein p-tau181 in the blood were associated with poorer memory and cognition at the follow-up stage.
"P-tau181 was not associated with memory at the initial assessment, but it was associated with memory performance six years later," says cognitive neurologist Deirdre O'Shea.
"That suggests these blood markers may provide information about future cognitive vulnerability that is not apparent from cognition measured at the same point in time."
An abnormal build-up of the tau protein is characteristic of brains with Alzheimer's, and past studies have suggested that similar proteins in the blood – such as p-tau181 – might be linked as well.
The researchers also tested for the biomarkers Aβ42/40 (associated with amyloid-beta protein plaques, another hallmark of Alzheimer's disease), GFAP (a marker of brain supporting cells called astrocytes), and NfL (which gets released into the blood when nerve fibers are damaged).
On the cognition side, the tests included assessments of memory, executive function, language, and visuospatial skills.
In the initial assessments, it was NfL and GFAP that were most strongly linked to cognition, including memory and executive function capabilities. By 2022, the picture had shifted: p-tau181 was linked to lower memory and global cognition scores, while GFAP was associated with poorer memory, poorer executive function, and overall cognition.
While most participants didn't have any cognitive issues at the start of the study period, some had been diagnosed with mild cognitive impairment or dementia. The main results from the data held even after the researchers analyzed the cognitive normal participants as a separate group.
"Blood biomarkers are often discussed as positive or negative tests, but biology exists on a continuum," says O'Shea.
"By examining biomarker levels across their full range and looking separately at memory, executive functioning and other cognitive abilities, we could see patterns that would be lost by reducing either the biomarker or cognition to a single category."
The findings suggest that a combination biomarker test looking for p-tau181 and GFAP may help identify people at a higher risk of developing cognitive issues over the next few years – though the researchers emphasize that the test wouldn't predict dementia.
In conclusion, the study team suggests there might not be a single 'best' blood test for spotting Alzheimer's early, but that different tests could be used to identify different biomarkers at a variety of ages.
Ways to build on the study could include tracking participants more continuously over time (with blood tests running alongside cognitive tests), and charting the p-tau181 and GFAP biomarkers against actual cases of Alzheimer's and other dementia types.
This study looked specifically at cognitive decline and the memory issues connected to dementia, rather than dementia itself, but the more of these early warning signs that researchers can gather, the more accurate the tests will become.
Related: The Roots of Dementia Trace Back All The Way to Childhood, Experts Reveal
"Together, these findings indicate that cognitive outcome, analytic context, and biomarker parameterization should be considered jointly when evaluating prognostic blood-based biomarker associations," write the researchers in their published paper.
The research has been published in Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring.
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