Linking Plasma p-tau217 to Brain Metabolism in Alzheimer Disease: Insights With Ana C. Pereira, MD

As blood-based biomarkers continue to gain momentum in Alzheimer disease (AD) research and clinical care, investigators are working to better understand how these measures relate to established markers of neurodegeneration. In a recently published study in Brain Communications, researchers led by Ana C. Pereira, MD, associate professor of neurology and neuroscience at the Icahn School of Medicine at Mount Sinai, examined the relationship between several plasma biomarkers and neuroimaging outcomes in patients with early symptomatic AD.

The analysis included phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and amyloid-related biomarkers, alongside fluorodeoxyglucose positron emission tomography (FDG-PET), structural MRI, cognitive testing, and plasma analyses. Through this multimodal approach, investigators sought to further characterize how blood-based biomarkers align with functional and structural changes in the brain, contributing to the growing evidence supporting their role in AD assessment.

To gain further insight into the findings, NeurologyLive^® sat down with Pereira. During the interview, she discussed the evolving landscape of blood-based biomarkers for AD and reviewed recent research exploring the relationship between plasma p-tau217 and cerebral glucose metabolism. She also highlighted the study's key findings, addressed notable limitations, and shared her perspective on future directions for biomarker development in AD.

NeurologyLive: Can you provide a general overview of the research you were a part of?

Pereira, MD: Over the past two decades, there has been substantial progress in the development of biomarkers for AD. These advances span multiple domains, including structural imaging, such as MRI, molecular imaging, such as amyloid and tau PET, fluid biomarkers measured in cerebrospinal fluid (CSF) and, more recently, plasma. Blood-based biomarkers are particularly promising because they can be readily integrated into routine clinical workflows.

They offer a scalable approach to support earlier diagnosis, facilitate screening for emerging anti-amyloid therapies, and streamline research by identifying appropriate participants for clinical trials in a more efficient and cost-effective manner. It is essential to interpret all biomarkers within the broader clinical context, including the patient’s history, neurologic examination, cognitive assessment, brain imaging, and molecular data such as blood-based biomarkers.

As plasma biomarkers move closer to widespread clinical implementation, I contributed to a Global CEO Initiative on an AD workgroup alongside Suzanne Schindler, MD, PhD, Oskar Hansson, MD, PhD, and others. Our 2024 publication in Nature Reviews Neurology outlined acceptable performance criteria for blood-based tests detecting amyloid pathology in both primary care and behavioral neurology settings.

Building on these efforts, our lab at Mount Sinai School of Medicine in New York City has recently published a study in Brain Communications titled “Plasma p-tau217 and glucose metabolism correlate in neocortical association areas in Alzheimer’s disease,” which further explores the relationship between plasma biomarkers and neurodegenerative processes in the brain.

Why is it important to conduct research of this nature and what gaps in AD detection does this study aim to highlight?

We asked the following question: how do plasma biomarkers relate to brain function and cerebral metabolism? While many studies have examined the relationship between plasma AD biomarkers and amyloid or tau PET imaging, far less is known about how these markers reflect brain metabolism, functional changes, and their regional specificity.

To address this gap, we used FDG-PET imaging—a technique that measures cerebral glucose metabolism—as a proxy for neuronal activity as glucose is the primary energy source in the brain. We then examined FDG-PET relationship with several plasma biomarkers such as Ptau 217, ptau 181, ptau 231,GFAP, Abeta 42/40, NfL in participants with mild Alzheimer’s disease, with the goal of identifying how circulating blood markers correspond to metabolic changes across specific brain regions.

Can you explain the results and their clinical significance?

We found that ptau217 correlates with hypometabolism in participants with mild AD in several neocortical areas such as lateral temporal cortex, the precuneus and inferior parietal cortex. These are critical brain areas for higher cognitive processing and information integration and very relevant in AD. We also observed more cortical atrophy in these brain regions accompanied by greater cognitive impairment.

We additionally observed that participants with equivalent biomarker levels still exhibited diverse patterns of FDG-PET and atrophy. This suggests that, despite the above correlations, imaging provides additional information. These findings support and extend our knowledge of how plasma p-tau217 relates to other AD biomarkers and cerebral metabolism, helping to contextualize both the benefits and limitations of these plasma biomarkers.

What are some of the limitations of this study?

One important limitation of the study was its relatively small sample size, and we plan to expand these analyses in larger cohorts moving forward. Another notable limitation relates to plasma storage. The samples were collected and stored many years ago, before the widespread use of plasma biomarkers in AD research and the establishment of current handling standards. As a result, variability in sample processing and storage conditions may have contributed to greater heterogeneity in the biomarker measurements."

In your mind, what needs to be studied further?

We need to expand the plasma biomarker landscape beyond core AD pathology to capture common co-pathologies, including α-synuclein and TDP-43. In parallel, there is a critical need for the discovery plasma biomarkers that can predict disease progression and identify patients at risk for amyloid-related imaging abnormalities in the context of anti-amyloid therapies.

Transcript edited for clarity.