Are we getting closer to being able to reliably quantify protein biomarker isoforms for neurodegenerative diseases in blood instead of cerebrospinal fluid (CSF)? According to Mari DeMarco, PhD, the answer is a resounding yes.

Thanks to advancements in analytical techniques such as mass spectrometry, measuring peripheral biomarkers for neurodegenerative disorders in cognitively impaired individuals does not necessarily require a dreaded lumbar puncture. New assays touting improved analytical sensitivity and reduced analytical interference are paving the road to transitioning from neurodegenerative CSF biomarkers to blood-based analytes.

In the session, “The Future is Near: Blood Tests for Alzheimer’s and Related Neurodegenerative Diseases,” developed in collaboration with the AACC Clinical Translational Science Division and the Proteomics and Metabolomics Division, DeMarco and Melissa Budelier, PhD, provide an update on several recently developed peripheral blood protein biomarkers and assays for neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease, Creutzfeldt-Jakob disease, frontotemporal dementia, and other major proteinopathies.

The need for new prognostic and diagnostic biomarkers for these diseases cannot be overstated. For AD alone, an estimated 1 in 10 individuals in the United States over the age of 65 suffer from the disease, with prevalence increasing with age. Existing AD biomarkers include CSF markers of amyloid-ß plaque accumulation, tau fibril formation, and neuronal damage.

While these CSF tests are used around the world to assist in making a diagnosis for complex/atypical cases of cognitive impairment, the requirement for lumbar puncture limits their application in other settings, such as, screening individuals for enrollment in clinical trials. Advanced and rapidly evolving analytical techniques have mitigated the challenges associated with the lower abundance of these markers in blood compared to CSF. Several blood-based AD biomarker assays are currently in development and they have potential use as screening and diagnostic tests in symptomatic individuals.

How will blood-based markers of AD and other neurodegenerative diseases enter the realm of clinical utility? DeMarco emphasizes the need to address the pre-analytical and analytical variables that impact this new landscape of assays. In the pre-analytical space, consideration should be given to the specimen collection process with a goal of minimizing the proteolytic degradation of peptides, which occurs at a higher rate in blood compared to CSF.

As research continues toward developing peripheral biomarkers and associated assays for neurodegenerative diseases, a key to bridging the translational divide between research and clinical utility will be including “clinically meaningful patient populations,” says DeMarco.

Biomarkers that differentiate between individuals with disease and healthy controls might be inadequate in the context of diagnosing neurodegenerative diseases in cognitively impaired individuals. Of particular importance will be developing biomarkers and associated assays that enable differentiation of neurodegenerative disorders with overlapping phenotypes, especially in the early stages of disease when diagnosis is challenging, but treatment potential is greatest. Achieving this goal will require enrolling and monitoring in observational and therapeutic clinical trials asymptomatic individuals or individuals with only mild symptoms.

The future is indeed near for blood-based biomarker assays for many neurodegenerative diseases. Advanced analytical techniques need to be coupled with certified reference materials and reference methods to standardize detection of these new biomarkers. Herein lies a winning formula to enable more rapid and efficient research and clinical trials for neurodegenerative disease prevention and treatment. The time is right for neurodegenerative disease biomarkers to take the leap from CSF to blood.