Are Tau PET Scans “Lighting Up” Too Much of the Brain?

Tau proteins play an important role in our normal brain function, mainly by helping to stabilize neurons in the brain. But in Alzheimer’s disease, tau proteins can misfold and tangle inside neurons. These tangles spread across the brain forming toxic clumps that impair neuronal function and ultimately lead to cell death.

PET scans are one of the few ways that clinicians and researchers can “see” Alzheimer’s disease biology in a living person. PET scans for tau are increasingly used in specialty clinics and research to estimate the burden and distribution of tau tangles, providing information that can influence diagnostic confidence, prognosis discussions, and to determine how patients are selected for novel Alzheimer’s therapies and tracked in Alzheimer’s drug trials.

At the same time, there is an important limitation to tau PET scans: the most widely used tau PET tracer (Flortaucipir/Tauvid) can also bind to other biological features in the brain, sometimes showing a low-level signal on scans even when tau is not the main driver of the results. This is especially true in non-Alzheimer’s disorders, where tau protein accumulations show a different structure than in Alzheimer’s disease.

In a study appearing Feb. 25 in Acta Neuropathologica, UC San Francisco researchers used a rare combination of patient tau PET imaging and detailed postmortem brain tissue mapping to clarify the extent to which non-tau factors influence the Flortaucipir tracer signal.

With the aid of AI-enabled voxel-by-voxel alignment between the PET scan and microscopy, the researchers computationally matched the PET signal to the corresponding tissue location and generated thousands of point-by-point comparisons per person, giving much higher anatomical precision than typical PET–autopsy studies.

They then measured, side-by-side, the tissue features most relevant to interpreting flortaucipir: tau pathology, ferric iron deposits, and MAO-B — a biomarker found in reactive astrocytes that is a key component of neuroinflammation. They found that in several non-Alzheimer’s tauopathies, the PET signal was better explained by iron and/or MAO-B–related processes than by tau itself.

“Our results help explain why tau PET scans sometimes ‘light up’ beyond what tau pathology alone would predict,” says co-senior author Lea T. Grinberg, MD, PhD, a former UCSF neuroscientist and current professor of Neuroscience at the Mayo Clinic. “In Alzheimer’s disease, tau is a major contributor to flortaucipir signal — but not the only one.”

The researchers believe these findings can help clinicians avoid over-interpretation of borderline signal in a tau PET scan and improve how scans are used for prognosis and trial decisions.

“This work doesn’t argue against tau PET, rather, it helps clinicians and researchers interpret it more accurately,” said co-senior author Gil Rabinovici, MD, the Edward Fein and Pearl Landrith Distinguished Professorship in Memory & Aging in the UCSF Department of Neurology. “By clarifying when and where the signal reflects tau versus other biology, the findings can support better clinical decision-making and can inform the development of next-generation tracers that are more specific.”

Additional Authors: Yuheng Chen, Renaud La Joie, Felipe L. Pereira, Ganna Blazhenets, Lucile Zhu, Salvatore Spina, William W. Seeley, Helmut Heinsen, Daniela Ushizima, Duygu Tosun

Funding: The work was supported by a research grant from Eli Lilly (Lilly Research Award Program) and NIA R01AG070826, NIA K24 AG053435 (Grinberg), P30 AG062422 (GDR), U01 AG057195, P01AG09724, and the Rainwater Charitable Foundation (GDR).

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