New study in cognitively healthy adults highlights the unique sensitivity of tau PET in the early stages of Alzheimer's

A new study led by the Barcelonaβeta Brain Research Center (BBRC) has shown that advanced brain imaging can detect the earliest biological signs of Alzheimer’s disease even in people who have no memory problems or clinical symptoms. The research demonstrates that tau PET scans detect subtle tau protein deposition, one of the key hallmarks of Alzheimer’s, at a stage when current blood-based tests are not yet sensitive enough to consistently detect these very early changes.

The findings, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, are based on the results of an investigation of 99 cognitively unimpaired adults participating in the ALFA+ cohort, part of the ALFA study (ALzheimer's and FAmilies) at the BBRC, supported by ”la Caixa” Foundation. ALFA+ follows individuals who are at increased risk of developing Alzheimer’s because of their family history or genetic factors and is considered one of the world’s most advanced research platforms for understanding the earliest phases of the disease.

Seeing Alzheimer’s pathology before symptoms emerge

This study presents the first tau PET findings from the ALFA+ cohort, expanding the project’s capacity to capture the earliest stages of Alzheimer’s pathology. Participants underwent a comprehensive set of evaluations, including a tau PET scan with ¹⁸F-RO-948, a second-generation tracer that detects tau at lower levels with greater accuracy than earlier tracers. They also completed an amyloid PET scan, high-resolution MRI, cognitive tests, and provided cerebrospinal fluid (CSF) and blood samples for biomarker analyses

The tau PET scans revealed that a proportion of these otherwise healthy adults already had measurable tau deposition, a hallmark that follows the amyloid accumulation, in brain regions typically affected in Alzheimer’s disease. These early changes followed the well-known Braak pattern, a sequence that describes how tau gradually spreads through the brain. Initially identified in postmortem studies, this pattern can now be observed in living, symptom-free individuals.

According to the research, these results support the concept that Alzheimer’s disease begins silently many years before the first signs of memory loss appear. By means of a PET scan, these very first stages of tau pathology can be visualized within people who are completely symptom-free. This is considered a crucial step in understanding when and how the disease begins, as well as in designing preventive strategies.

Blood biomarkers: powerful tools, with limits in the earliest stages

The study also examined how well CSF and blood biomarkers reflect the presence of early tau pathology. Among the CSF biomarkers analyzed, p-tau217 showed the strongest association with tau PET signal. In blood, p-tau217 emerged as the most informative biomarker, closely associated with tau-PET changes.

However, the researchers found that when tau pathology was still extremely subtle, as it is in many cognitively unimpaired individuals, blood-based biomarkers had limited ability to detect these early changes, underscoring the added value of tau PET at this stage.

According to the researchers, these results further support the idea that Alzheimer’s brain-related changes begin years before clinical symptoms emerge. “Our findings show that tau PET can detect early tau pathology in cognitively unimpaired individuals at risk for Alzheimer’s disease. The limited ability of the fluid biomarkers assessed in this study, including p-tau217, to identify these earliest changes highlights the value of tau PET for studying the earliest biological stages of the disease. It also underscores the need for more sensitive plasma biomarkers and may help refine cohort enrichment strategies and the design of prevention trials in preclinical Alzheimer’s disease”, says Dr. Mahnaz Shekari, lead author of the study. “In this early stage of the disease, when tau levels are still very low, its accumulation measured by PET scan appears to be more effective at predicting future cognitive decline than amyloid accumulation, whether assessed by PET or fluid biomarkers”, clarifies Dr. Juan Domingo Gispert.

Implications for early detection and future prevention

As mentioned by Dr. Gemma Salvadó, group leader of the Neuroimaging Research Group, “The study’s strength lies in its multimodal design in this early population. By combining brain imaging, fluid biomarkers, genetics, and cognitive assessments, we were able to create one of the most detailed pictures to date of how Alzheimer’s pathology emerges in the preclinical phase”.

The study highlights the value of well-characterized cohorts, such as the ALFA study, which follows participants for years using multimodal biomarkers, including brain imaging (PET and MRI), CSF, and plasma measures. These longitudinal insights platforms are crucial for understanding how Alzheimer’s disease develops and for advancing early diagnosis and prevention strategies.

Together, these findings reinforce the idea that early detection will likely rely on a combination of approaches tailored to the disease stage.

Reference article: Shekari M, Escalante AG, Milà-Alomà M, et al. Associations of 18F-RO-948 tau PET with fluid AD biomarkers, Centiloid, and cognition in early AD continuum. Alzheimer's Dement. 2026;22:e71176. https://doi.org/10.1002/alz.71176