P-Tau: A Promising Blood-Based Biomarker

By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health

Early and accurate diagnosis of Alzheimer’s disease (AD) is crucial for effective treatment and management. For the first time, blood tests are available that will aid in the early detection and monitoring of AD. One such promising blood biomarker is p-tau, a specific isoform of tau protein.

Microtubules are major components of the cytoskeleton and are involved in cell division, cell motility, intracellular transport, and maintenance of cell shape. One of the major roles of microtubules is to transport membrane vesicles and organelles through the cytoplasm of eukaryotic cells — thus, microtubules effectively are the cell’s ‘freeway’ system. Such an intricate cytoplasmic organelle transport is particularly evident in neurons, which may extend more than a meter in length. Neuronal transport is driven by specialized molecular motors that run on a specific track — the ‘highway/freeway’ formed by microtubules. Using this transport system, molecular motors deliver building blocks and other needed materials to other parts of the cell or other cells.

In the brain, tau protein plays an important role as a primary neuronal microtubule protein. In a healthy brain, tau molecules assemble with each other and form a compact structure that allows molecular motor proteins like kinesin to move effortlessly, thereby facilitating the transport of essential nutrients from one part of the nerve cell to another. This tight assembly is made possible through a chemical modification process called phosphorylation, which involves the attachment of a phosphate group to a protein molecule — in this case, tau.  This process and its reverse, dephosphorylation (aka removal of the phosphate group), is commonly seen as part of a biological reaction that activates or deactivates protein function.

In the case of tau, phosphorylation on several sites helps to promote efficient microtubule assembly and maintain the compact ‘freeway’ structure. It is normal for neurons to have a stable and long-lived phosphorylated tau protein to support cellular transport and maintain cell structure.  In contrast, for reasons that are still unclear, tau protein sometimes undergoes excessive or aberrant phosphorylation (aka hyperphosphorylation), which weakens the compact ‘freeway’ structure. This is seen in neurons from people with Alzheimer’s disease. In this scenario, tau proteins are ‘unstable and less compact’ than the neurons of individuals without the disease. Researchers suspect that having two copies of ApoE4 and/or events such as head trauma, rogue genes, infections, or other environmental factors could trigger hyperphosphorylation of tau, which results in the disassembly of tau’s compact structure and breakdown of the microtubular freeway system. This disrupts the microtubule transport, leading to synaptic dysfunction and cognitive deficits.

Interestingly, researchers have noticed that older adults with intact cognition but with significant amounts of hyperphosphorylated tau are much more likely to develop cognitive impairment or dementia within a few years. The finding highlights the critical role of tau in disease progression. It suggests that tau hyperphosphorylation may be an early event prior to the onset of AD symptoms and could serve as an early predictor of AD onset. Early detection is extremely important to help delay AD progression and for interventions to be successful.

To optimize existing blood-based biomarker testing, researchers have now developed special antibodies that selectively bind to phosphorylated tau. Plasma levels of phosphorylated tau appear to be a strong predictor of cognitive decline in preclinical and prodromal disease stages. Compared to other detection methods like positron emission tomography (PET) or lumbar puncture for cerebrospinal fluid (CSF) tau, which are expensive, invasive, and lack wide availability, blood p-tau has emerged as a top-performing biomarker for AD pathology, enabling clinical sensitivity and specificity in blood. It also offers the advantage of greater availability and tolerability for both clinicians and patients. Though the blood p-tau test is not meant to make a definitive diagnosis of AD pathology, the test’s results will help clinicians evaluate whether a patient with suspected cognitive impairment is also experiencing any of the biological changes linked to AD — thereby potentially speeding up the time it takes to order other tests, reach a diagnosis and begin treatment for the disease. Apollo Health is working with a few labs to offer blood p-tau and several other promising markers at a discounted price. Be the first to be notified when the test is available so you can assess your risk.