A blood biomarker that measures astrocyte reactivity may help determine who, among cognitively unimpaired older adults with amyloid-beta, will go on to develop Alzheimer's disease (AD), new research suggests.
Investigators tested the blood of 1000 cognitively healthy individuals with, and without, amyloid-beta pathology and found that only those with a combination of amyloid-beta burden and abnormal astrocyte activation subsequently progressed to AD.
"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," senior investigator Tharick A. Pascoal, MD, PhD, associate professor of psychiatry and neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, said in a release.
At this point, the biomarker is a research tool, but its application in clinical practice "is not very far away," Pascoal told Medscape Medical News.
The study was published online May 29 in Nature Medicine.
In AD, accumulation of amyloid-beta in the brain precedes tau pathology, but not everyone with amyloid-beta develops tau, and, consequently, clinical symptoms. Approximately 30% of older adults have brain amyloid but many never progress to AD, said Pascoal.
This suggests other biological processes may trigger the deleterious effects of amyloid-beta in the early stages of AD.
Finding predictive markers of early amyloid-beta–related tau pathology would help identify cognitively normal individuals who are more likely to develop AD.
Post-mortem studies show astrocyte reactivity — changes in glial cells in the brain and spinal cord because of an insult in the brain — is an early AD abnormality. Other research suggests a close link between amyloid-beta, astrocyte reactivity, and tau.
In addition, evidence suggests plasma measures of glial fibrillary acidic protein (GFAP) could be a strong proxy of astrocyte reactivity in the brain. Pascoal explained that when astrocytes are changed or become bigger, more GFAP is released.
The study included 1016 cognitively normal individuals from three centers; some had amyloid pathology, some did not. Participants' mean age was 69.6 years and all were deemed negative or positive for astrocyte reactivity based on plasma GFAP levels.
Results showed amyloid-beta is associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity. In addition, analyses using PET scans showed an AD-like pattern of tau tangle accumulation as a function of amyloid-beta exclusively in those same individuals.
Early Upstream Event
The findings suggest abnormalities in astrocyte reactivity is an early upstream event that likely occurs prior to tau pathology, which is closely related to the development of neurodegeneration and cognitive decline.
It's likely many types of insults or processes can lead to astrocyte reactivity, possibly including COVID, but more research in this area is needed, said Pascoal.
"Our study only looked at the consequence of having both amyloid and astrocyte reactivity; it did not elucidate what is causing either of them," he said.
Although "we were able to have very good results" in the current study, additional studies are needed to better establish the cut-off for GFAP levels that signal progression, said Pascoal.
The effect of astrocyte reactivity on the association between amyloid-beta and tau phosphorylation was greater in men than women. Pascoal noted anti-amyloid therapies, which might be modifying the amyloid-beta-astrocyte-tau pathway, tend to have a much larger effect in men than women.
Further studies that measure amyloid-beta, tau, and GFAP biomarkers at multiple timepoints, and with long follow-up, are needed, the investigators note.
The results may have implications for clinical trials, which have increasingly focused on individuals in the earliest preclinical phases of AD. Future studies should include cognitively normal patients who are positive for both amyloid pathology and astrocyte reactivity but have no overt p-tau abnormality, said Pascoal.
This may provide a time window for interventions very early in the disease process in those at increased risk for AD-related progression.
The study did not determine whether participants with both amyloid and astrocyte reactivity will inevitably develop AD, and to do so would require a longer follow up. "Our outcome was correlation to tau in the brain, which is something we know will lead to AD."
Although the cohort represents significant socioeconomic diversity, a main limitation of the study was that subjects were mainly White, which limits the generalizability of the findings to a more diverse population.
The study received support from the National Institute of Aging; National Heart Lung and Blood Institute; Alzheimer's Association; Fonds de Recherche du Québec-Santé (FRQS); Canadian Consortium of Neurodegeneration in Aging; Weston Brain Institute; Colin Adair Charitable Foundation; Swedish Research Council; Wallenberg Scholar; BrightFocus Foundation; Swedish Alzheimer Foundation; Swedish Brain Foundation; Agneta Prytz-Folkes & Gösta Folkes Foundation; European Union; Swedish State Support for Clinical Research; Alzheimer Drug Discovery Foundation; Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden; the UK Dementia Research Institute at UCL; National Academy of Neuropsychology; Fundação de Amparo a pesquisa do Rio Grande do Sul; Instituto Serrapilheira; Hjärnfonden.
Pascoal reports no relevant financial relationships.
Nat Med. Published online May 29, 2023. Full text
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Cite this: Blood Biomarker May Help Predict Who Will Develop Alzheimer's - Medscape - Jun 06, 2023.