Advancements in Alzheimer’s Research: Newly Identified Blood Biomarker

The progression of Alzheimer’s disease seems to be significantly affected by star-shaped brain cells, known as astrocytes, as shown in a study by the University of Pittsburgh School of Medicine. While previously amyloid aggregates were regarded as the primary instigator of Alzheimer’s, this latest research indicates that the combination of amyloid deposits and abnormal activation of astrocytes, as identified by blood markers, predicts the forthcoming onset of symptomatic Alzheimer’s. This finding challenges the existing belief that amyloid alone instigates the disease.

Researchers have long struggled with the questions of what factors lead to an individual developing Alzheimer’s disease and why some with the disease’s toxic amyloid build-ups in the brain never show related dementia symptoms.

New insights have been revealed in a study from the University of Pittsburgh School of Medicine. This groundbreaking research published in Nature Medicine suggests that astrocytes, star-shaped brain cells, are instrumental in the progression of Alzheimer’s disease.

In this study, researchers analyzed the blood of over a thousand cognitively healthy elderly individuals, both with and without amyloid pathology. The Pitt-led team discovered that only those with both amyloid deposits and blood markers indicating abnormal astrocyte activation would develop symptomatic Alzheimer’s in the future. This discovery is crucial for future drug development aiming to halt disease progression.

Senior author Tharick Pascoal, M.D., Ph.D., associate professor of psychiatry and neurology at Pitt, stated, “Our research contends that checking for brain amyloid along with blood biomarkers of astrocyte reactivity optimally identifies patients most at risk for progressing to Alzheimer’s disease. This positions astrocytes as key disease progression regulators, contesting the idea that amyloid alone initiates Alzheimer’s disease.”

Alzheimer’s disease, a neurodegenerative condition, progressively impairs memory and cognitive functions, significantly reducing patients’ quality of life. At the cellular level, Alzheimer’s is characterized by accumulations of amyloid plaques—protein aggregates lodged between nerve cells in the brain—and clumps of disordered protein fibers, known as tau tangles, forming inside neurons.

Previously, brain scientists held the belief that the accumulation of amyloid plaques and tau tangles was not only an indication of Alzheimer’s but also its primary cause. This belief drove pharmaceutical companies to invest heavily in molecules targeting amyloid and tau, while potentially overlooking other crucial brain processes like the neuroimmune system.

Recent breakthroughs, such as Pascoal’s research, propose that the disruption of other brain processes, like elevated brain inflammation, may be as pivotal as the amyloid burden in setting off the destructive cascade of neuronal death leading to rapid cognitive decline.

In prior research, Pascoal and his team discovered that brain tissue inflammation triggers the spread of pathologically misfolded proteins in the brain, causing cognitive impairment in Alzheimer’s patients. Now, almost two years later, they have unveiled that cognitive impairment can be predicted by a blood test.

Astrocytes, specialized cells plentiful in the brain, like other glial cells—the resident immune cells of the brain—support neuronal cells by providing them with nutrients, oxygen, and protection from pathogens. However, because glial cells don’t conduct electricity and didn’t initially seem to play a direct role in neuron communication, their significance in health and disease had been underestimated. This new research from Pitt has challenged this view.

Lead author of the study Bruna Bellaver, Ph.D., a postdoctoral associate at Pitt, said, “Astrocytes orchestrate the relationship between brain amyloid and tau, akin to a conductor guiding an orchestra. This could revolutionize the field, as glial biomarkers are generally not considered in any major disease model.”

The scientists tested blood samples from participants in three independent studies of cognitively unimpaired elderly people for biomarkers of astrocyte reactivity, namely glial fibrillary acidic protein (GFAP), along with the presence of pathological tau. The study revealed that only those who tested positive for both amyloid and astrocyte reactivity showed signs of progressively developing tau pathology, indicating a predisposition to clinical symptoms of Alzheimer’s disease.

The research results have profound implications for future Alzheimer’s clinical trials. To halt disease progression earlier, trials are focusing on increasingly earlier stages of pre-symptomatic disease. Hence, accurate early diagnosis of Alzheimer’s risk is vital for success. As amyloid positivity alone is insufficient to determine an individual’s eligibility for therapy, the inclusion of astrocyte reactivity markers, such as GFAP, in the panel of diagnostic tests will enhance the selection process of patients likely to progress to later stages of Alzheimer’s. Consequently, it will help refine the selection of candidates for therapeutic interventions who are most likely to benefit.

This study was supported by the National Institute on Aging and the Alzheimer’s Association.

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More about Alzheimer’s disease research

• University of Pittsburgh School of Medicine: Link
• Nature Medicine: Link