Blood test may be able to identify those at risk of Alzheimer’s
Test checks for abnormal activation of star-shaped brain cells called astrocytes
A blood test that checks for the abnormal activation of star-shaped cells in the brain called astrocytes may be able to identify people who are more likely to develop Alzheimer’s disease, a new study suggests.
“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” Tharick Pascoal, MD, PhD, the study’s senior author and an associate professor of psychiatry and neurology at the University of Pittsburgh (Pitt), said in a press release.
“This puts astrocytes at the center as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer’s disease,” Pascoal added.
The study, “Astrocyte reactivity influences amyloid-[beta] effects on tau pathology in preclinical Alzheimer’s disease,” was published in Nature Medicine.
Astrocytes act like ‘conductor directing the orchestra’
Alzheimer’s is marked by toxic clumps of the amyloid-beta protein and of the tau protein in the brain. It’s thought that amyloid-beta aggregates form first, followed by tau clumps, and their spread through the brain helps to drive disease progression.
However, amyloid-beta clumps are also detectable in many people who don’t have any tau aggregates and consequently no cognitive symptoms associated with Alzheimer’s. Some people with these clumps will eventually develop Alzheimer’s and tau clumps, but others won’t, and the reason for this difference has been a mystery.
Emerging research suggests the difference may lie in astrocytes. These cells serve a number of important functions in the nervous system, helping to support nerve cell health.
However, in neurodegenerative diseases like Alzheimer’s, they are known to enter an injury-associated state, known as astrocyte reactivity, that can have damaging effects and contribute to further neurodegeneration.
Preclinical studies have suggested that astrocyte reactivity is key for amyloid-beta-induced tau phosphorylation, a chemical modification that makes it more prone for aggregation, “and that the attenuation of astrocyte reactivity mitigates tau [abnormalities],” the researchers wrote.
“Astrocytes coordinate brain amyloid and tau relationship like a conductor directing the orchestra,” said Bruna Bellaver, PhD, the study’s first author and a postdoctoral associate at Pitt.
Here, researchers tested whether measuring levels of GFAP, a marker of astrocyte reactivity, could help identify people with amyloid-beta clumps who will develop Alzheimer’s. A total of 1,066 people without any signs of cognitive impairment were included in the study.
This puts astrocytes at the center as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer’s disease.
Based on GFAP levels, 743 people were classified as negative for astrocyte reactivity, while the remaining 273 were classified as astrocyte reactivity-positive.
More than half (52.3%) were negative both for amyloid-beta clumps and astrocyte reactivity. There were also 165 patients (15.5%) who were positive for astrocyte reactivity but negative for amyloid-beta aggregates. Among participants who had amyloid-beta clumps, 186 were negative for astrocyte reactivity and 108 were positive.
Statistical analyses showed a significant association between higher amyloid-beta aggregate levels and higher phosphorylated tau levels in astrocyte reactivity-positive participants, with stronger correlations seen in men than women.
However, levels of these two disease markers were not significantly correlated in people without astrocyte reactivity.
Analyses of brain scans from 147 participants showed that amyloid-beta levels were significantly associated with those of phosphorylated tau “only in the presence of astrocyte reactivity in some brain regions previously shown to present early [amyloid-beta abnormalities],” the researchers wrote.
In analyses of 71 patients followed for more than two years on average, tau clumps accumulated significantly faster in astrocyte reactivity-positive people.
This suggests that people with both beta-amyloid clumps and astrocyte reactivity may be at a higher risk of developing Alzheimer’s clinical symptoms.
Findings may have implications for selecting participants for clinical trials
Collectively, these data “shows that increased astrocyte reactivity, as indicated by elevated plasma [blood] GFAP, plays a role in the association of [amyloid-beta] with early tau phosphorylation in preclinical AD [Alzheimer’s disease],” the researchers wrote. Preclinical disease comprises the stages preceding Alzheimer’s symptoms.
“These results suggest that astrocyte reactivity abnormality could be placed as an early upstream event, likely before tau [abnormalities], in the hypothetical biomarker models of AD progression,” the researchers added, though they noted that further studies tracking these markers over time are needed to confirm this idea.
This finding could be “a game-changer to the field,” Bellaver said, noting that markers of astrocytes and other types of nervous tissue-support cells, known as glia, “in general are not considered in any main disease model.”
The study’s results “may have implications for the biological definition of preclinical AD and for selecting [cognitively normal] individuals for clinical trials,” the team wrote.