Daniel Martinez-Perez, Ph.D. candidate in Tomás R. Guilarte's lab at FIU, holds a brain tissue sample from a person with the Paisa Alzheimer's mutation. (Credit: Chris Necuze)

Can we detect Alzheimer’s disease decades before symptoms start?

Research reveals a promising new target to thwart Alzheimer’s in its tracks

Science & Technology

By Angela Nicoletti

September 9, 2025 at 10:30am

A person will have Alzheimer’s years before ever knowing it. The disorientating erasure of memories, language, thoughts — in essence, all that makes up one’s unique sense of self — is the final act of this enigmatic disease that spends decades disrupting vital processes and dismantling the brain’s delicate structure.

Once symptoms surface and doctors make a diagnosis, though, it can often be too late. Damage is widespread, impossible to reverse. No cure exists.

Attempts to develop drugs that clear away toxic accumulations of amyloid-beta and tau proteins — hallmarks of the disease that cause neurons to die — have ended in hundreds of failed clinical trials. Today, some scientists are skeptical over whether removing amyloid plaques is even enough. Others have a hunch that the best line of attack won’t target just one aspect of the disease, but many of them, all at once.

Tomás R. Guilarte, who leads a brain health research group at FIU, is looking at one of those targets: TSPO. It may not only be among the earliest Alzheimer’s biomarkers — detectable before memory loss or cognitive decline — but a promising pathway to thwart chronic, damaging inflammation, according to the team’s latest study published in top neurology journal Acta Neuropathologica.

“Neuroinflammation is a very early event in Alzheimer’s that influences its onset,” says Guilarte, dean of FIU’s Robert Stempel College of Public Health & Social Work.

“If we can use TSPO to detect it early, right at the beginning stages of the disease, it could mean slowing progression or delaying symptoms by five or six years. That’s five or six years where someone has a better quality of life.”

Normally, in the brain, TSPO (or translocator protein 18 kDa) is present at very low levels.

But when the brain’s delicate balance is thrown off, like when there is neuroinflammation, it increases and keeps on increasing, Guilarte explains. And it keeps spreading and spreading.

On PET scans, it can look like the brain is on fire. TSPO shows up as a vivid red-orange hue.

TSPO in brains — *Guilarte's previous study, published in JAMA Neurology,* *showed TSPO levels were higher in active and recently retired NFL players ranging in age from 23 to 39.*

Guilarte has a long history with TSPO — among a handful of scientists who helped validate it as a biomarker of neuroinflammation. This work started in the 1990s when he was at Johns Hopkins University. Now, clinicians and researchers at major medical centers around the world rely on TSPO to track neuroinflammation not only in neurodegenerative but neurological and psychiatric diseases.

This latest study provides a never-before-seen look at TSPO.

For the first time, with the help of state-of-the-art imaging technology, Guilarte’s team was able to pinpoint where and when TSPO initially appears in the brain.

They found it coincides with the first appearance of small scatterings of amyloid plaques in the subiculum, part of the hippocampus, a brain structure critically important for learning and memory.

Then, they zoomed in to see what specific glial cells — including microglia and astrocytes, which are responsible for protecting neurons — were giving off the TSPO signals.

What you'll learn in this story

TSPO, a key biomarker in neuroinflammation, could help detect Alzheimer's disease years before memory loss or other symptoms appear — potentially leading to advances in how the disease is diagnosed and treated, according to new research.
TSPO levels first rise in the subiculum — a critical part of the hippocampus — as early as six weeks of age in a mouse model, roughly equivalent to age 18–20 in humans.
Findings were confirmed using human brain tissue donated by members of the world’s largest group of individuals with early-onset familial Alzheimer’s, located in Antioquia, Colombia.

TSPO in neuron — *L: The original cell image. R: The same cell image zoomed in and rendered in the special imaging software. Microglia (blue) signaling TSPO (red) are clustered around plaques (cyan).*

A new detail emerged: Microglia in closest proximity to amyloid plaques had the highest concentration or volume of TSPO.

Those cells expressed TSPO as early as one and a half months of age in a mouse model of Alzheimer’s disease — the equivalent of an 18- to 20-year-old human. Notably, female mice had higher TSPO levels, mirroring real-world statistics: two-thirds of Alzheimer’s patients are women. Declines in cognition happened five months later as plaques spread into other brain areas and TSPO levels continued to skyrocket.

“We didn’t see any TSPO increase in the other glial cells, like the astrocytes, which reveals the microglia are driving the majority of the inflammatory response,” Guilarte says. “What we believe is happening is something goes wrong with the microglia. They stop doing their job in removing the plaques and just keep sending out TSPO signals. This constant signal of neuroinflammation is like adding wood to a fire.”

Human brain tissue from Alzheimer’s subjects showed the same pattern.

Samples were donated by patients from Medellín and other mountain villages in northwest Colombia, where an estimated 1,200 have inherited a rare form of Alzheimer's disease. Typically, those impacted show symptoms as early as their 30s and 40s. And die in their 50s.

The late Francisco Lopera — a pioneering neurologist, who identified the genetic cause of the extended family’s disease, known as the Paisa mutation — collaborated with Guilarte’s team on this study.

“This work and our future projects would not be possible without our collaborators in Colombia, the patients and their families that make an essential contribution to study Alzheimer’s,” says Daniel Martinez-Perez, first author of the study and a doctoral candidate in Guilarte’s research group. “Dr. Lopera was really interested in finding ways to prevent this disease, among them the role of neuroinflammation and other mechanisms of Alzheimer's, so we are so proud to carry on the legacy of his life's work with this study.”

Daniel Martinez-Perez and Tomás Guilarte led a new study on how TSPO could help detect Alzheimer’s disease years before memory loss and other symptoms set in. (Credit: Chris Necuze)

Guilarte acknowledges there are some limitations, since the team was focused on genetic, early-onset cases. Nevertheless, decades spent studying neurodegenerative diseases makes him fairly confident that neuroinflammation plays a major role in all Alzheimer’s cases — both early-onset and late-onset, sporadic cases.

Martinez-Perez has already started the next stage of research. He’s currently examining human brain samples of late-onset cases, from the same Neuroscience Group at the Universidad de Antioquia’s brain bank.

“One of the biggest problems with Alzheimer’s is people see it as a disease of aging and that impacts when people get diagnosed,” Martinez-Perez says. “But the reality is that the disease starts decades before diagnosis and the more biomarkers and therapeutic targets our global community of scientists are finding, the closer we all get to physicians having a whole panel of diagnostics to be able to deliver more personalized, tailored treatments. My hope is we can be part of helping people before they are too sick.”