Scientists from the University of Pittsburgh School of Medicine have made a groundbreaking discovery about Alzheimer's disease. Their research suggests that star-shaped brain cells known as astrocytes play a crucial role in the progression of the disease, according to a study published in Nature Medicine.
In their study, the research team examined the blood of over 1,000 elderly individuals with and without cognitive impairments. They found that only those who had both amyloid burden (indicative of Alzheimer's brain pathology) and blood markers indicating abnormal activation or reactivity of astrocytes were likely to develop symptomatic Alzheimer's in the future. This finding is significant for the development of drugs aimed at stopping disease progression.
Senior author Tharick Pascoal, M.D., Ph.D., associate professor of psychiatry and neurology at the University of Pittsburgh, explained the implications of their study, stating, "Our study suggests that the optimal screening to identify patients who are most at risk for progressing to Alzheimer's disease is to test for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity. This puts astrocytes at the center as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer's disease."
Alzheimer's disease is a neurodegenerative condition that causes memory loss and dementia. It is characterized by the accumulation of amyloid plaques (protein aggregates) and tau tangles (disordered protein fibers) in the brain. Traditionally, scientists believed that these plaques and tangles were not only signs of Alzheimer's disease but also the direct cause. Consequently, drug development efforts have primarily targeted amyloid and tau while overlooking other brain processes, such as the neuroimmune system.
Recent discoveries, including previous research by Pascoal and his team, have indicated that other brain processes, such as increased brain inflammation, may play a significant role in initiating the cascade of neuronal death and cognitive decline seen in Alzheimer's. In their earlier work, they found that brain tissue inflammation triggers the spread of misfolded proteins in the brain and directly contributes to cognitive impairment in Alzheimer's patients. Now, their new research reveals that cognitive impairment can be predicted through a blood test.
Astrocytes are specialized cells that are abundant in brain tissue. They provide support to neuronal cells by supplying nutrients, oxygen, and protection against pathogens. However, the role of astrocytes and other glial cells in brain health and disease has been overlooked because they do not conduct electricity and were initially not considered to have a direct role in neuronal communication. This latest research challenges that perspective.
Lead author of the study, Bruna Bellaver, Ph.D., a postdoctoral associate at the University of Pittsburgh, explained the significance, saying, "Astrocytes coordinate brain amyloid and tau relationship like a conductor directing the orchestra. This can be a game-changer in the field, as glial biomarkers in general are not considered in any main disease model."
The researchers analyzed blood samples from participants in three independent studies involving elderly individuals without cognitive impairments. They examined biomarkers of astrocyte reactivity, specifically a protein called glial fibrillary acidic protein (GFAP), along with the presence of pathological tau. The study demonstrated that only individuals who tested positive for both amyloid and astrocyte reactivity showed evidence of progressive tau pathology, indicating a predisposition to clinical symptoms of Alzheimer's disease.
These findings have direct implications for future clinical trials of potential Alzheimer's drugs. As trials aim to intervene at earlier stages of the disease, accurate early diagnosis of Alzheimer's risk becomes crucial. Merely testing for amyloid positivity is insufficient, as a significant number of individuals with amyloid burden
do not progress to clinical forms of the disease.
By incorporating astrocyte reactivity markers, such as GFAP, into the diagnostic tests, researchers can better identify patients who are likely to progress to later stages of Alzheimer's. This would enhance the selection of candidates for therapeutic interventions, increasing the chances of benefiting from the treatments.
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