Brain inflammation protein TSPO may flag Alzheimer's risk years before symptoms, study suggests

A brain protein linked to inflammation could reveal a person’s risk of developing Alzheimer’s disease years before symptoms appear, according to new research from Florida International University. The study focused on TSPO, a protein used as an imaging marker of brain inflammation, to determine when and where its levels rise in life. Researchers studied mice genetically engineered to carry human gene mutations that increase Alzheimer’s risk and then examined brain tissue donated by members of Colombia’s Paisa family, a community known for a form of early-onset Alzheimer’s. The work aims to map the timeline of inflammatory signals in the brain long before memory and cognition are affected, with implications for early detection and potential prevention strategies.

In the mouse models, elevated TSPO appeared in the subiculum, a key part of the hippocampus involved in memory processing, as early as six weeks of age—roughly equivalent to humans in their late teens or early twenties. Microglia, the brain’s immune cells that cluster around amyloid plaques, showed the highest TSPO levels. The researchers also noted a gender difference: female mice tended to have higher TSPO levels, mirroring real-world observations that about two-thirds of Alzheimer’s patients are women. The study’s design included comparing animal findings with brain tissue from Colombian patients carrying a rare mutation known as PSEN1 E280A, part of the Paisa lineage, which almost reliably leads to early-onset Alzheimer’s. The parallel pattern in humans reinforced the idea that elevated TSPO could mark an increased risk years before clinical symptoms appear.

The Colombian brain samples exhibited the same TSPO elevation in regions associated with memory, suggesting that brain inflammation is not just a downstream consequence but may be an early driver of disease in people with strong genetic risk. Lead researcher Dr. Tomás Guilarte, an internationally recognized expert on TSPO, said this is the first study to really examine how early this biomarker increases and where it begins rising in the brain. “If we can use this information to help delay Alzheimer’s progression by even five years, it can drastically improve patients’ lives and reduce disease prevalence,” Guilarte said. He has studied TSPO for more than three decades and helped establish it as a reliable imaging biomarker for brain inflammation across a range of neurodegenerative and psychiatric conditions.

Daniel Martínez Pérez, the study’s first author and a Ph.D. candidate in Guilarte’s lab, noted that the findings align with a broader view that Alzheimer’s starts decades before diagnosis. He added, “The more biomarkers and therapeutic targets our global community of scientists are finding, the closer we get to physicians delivering more personalized, tailored treatments.” He emphasized that understanding the early role of TSPO could enable clinicians to intervene before extensive brain damage occurs and possibly delay the onset of symptoms by years.

The team is now pursuing experiments in a specially developed Alzheimer’s mouse model lacking TSPO to determine whether the protein contributes to disease progression or serves a protective role. They are also expanding the study to include sporadic, late-onset Alzheimer’s, the form that accounts for more than 90 percent of cases. In Guilarte’s view, clarifying TSPO’s function could determine whether therapies should aim to block or modulate the protein’s activity as part of early intervention strategies.

Alzheimer’s disease is one of the most common forms of dementia and primarily affects adults 65 and older. In the United States, about 7 million people in that age group live with the condition, and more than 100,000 die annually from Alzheimer’s-related complications. The Alzheimer’s Association projects that by 2050, nearly 13 million Americans could be living with the disease. Early-onset Alzheimer’s—diagnosed before age 65—accounts for roughly 5 percent of cases and often runs in families, sometimes due to inherited gene mutations. When it appears earlier, the disease tends to progress more rapidly, and the death toll can be disproportionately high because affected individuals are younger.

The study’s authors caution that the findings are early and primarily based on a mouse model and a small set of human brain samples. Still, the results add to a growing body of evidence that brain inflammation precedes clinical symptoms and could serve as an early target for diagnosis and intervention. The researchers hope their work will contribute to a future in which a panel of biomarkers enables physicians to identify people at elevated risk well before cognitive decline becomes apparent, potentially enabling preventive treatments that could delay onset and improve quality of life for patients and families.

In the broader context of Alzheimer’s research, experts say progress toward early detection and prevention remains challenging but essential. The current study underscores the importance of continued work to understand the mechanisms linking inflammation to neurodegeneration and to translate these insights into safe, effective therapies. As the population ages, identifying high-risk individuals earlier could reshape how clinicians approach prevention, care planning and resource allocation for a disease that already imposes a substantial burden on patients, families and health systems.