Blood Biomarkers for Alzheimer's Disease: Breaking Down The Research

The pathological changes associated with Alzheimer’s disease begin as early as 10 to 20 years before the onset of clinical symptoms. The ability to detect these changes early in the disease continuum is crucial not only for early diagnosis and early treatment of patients but also for monitoring therapeutic response and disease progression in clinical trials. 

Obtaining an accurate Alzheimer’s disease diagnosis is necessary for meeting key inclusion criteria. Currently, this is accomplished via molecular biomarkers in cerebrospinal fluid (CSF) and/or positron emission tomography (PET) scans. While highly accurate, the high cost, invasive nature, and low availability of these diagnostic procedures hamper their feasibility.

In this article, we will discuss the emergence of blood biomarkers for Alzheimer's disease and neurodegeneration and their future role in research and clinical trials.

Blood Biomarkers for Alzheimer’s Disease

Alzheimer’s and other neurodegenerative diseases are notoriously difficult to diagnose clinically. As such, biomarkers of the underlying pathophysiology play a crucial role in research, clinical trials, and the clinical work-up of patients.

For many years, blood biomarkers for Alzheimer’s disease were seemingly unattainable. However, thanks to great strides toward ultra-sensitive assays, blood-based tests are becoming a reality.

Alzheimer's disease is most commonly characterized by two defining features: beta-amyloid plaques and neurofibrillary tangles resulting from abnormal tau hyperphosphorylation. 

• Beta-amyloid plaques: Amyloid plaques are extracellular deposits of beta-amyloid peptides and are a distinct pathology of Alzheimer’s. Beta-amyloid proteins originate from a larger protein, amyloid precursor protein, found in the fatty membrane surrounding the nerve cells. Beta-amyloid is produced in all individuals and is naturally removed by the body before it can become harmful to the brain. However, for individuals with Alzheimer’s disease, it is not removed, and the beta-amyloid proteins stick or clump together, eventually forming a plaque that cannot be broken down. Beta-amyloid proteins begin to collect in the brains of individuals with Alzheimer’s disease up to 20 years before symptoms appear. 
• Tau tangles: Tau, a microtubule-associated protein, is normally located on the axon and plays a helpful role in the brain, physiologically facilitating axonal transport by binding and stabilizing microtubules that help guide nutrients and molecules from the cell body to the axon and dendrites. However, in individuals with Alzheimer’s disease, tau becomes altered and forms neurofibrillary tangles within nerve cells up to 15 years before symptom onset.

Emerging research suggests that concentrations of amyloid and phosphorylated tau proteins are associated with the corresponding concentrations of CSF as well as amyloid-PET and tau-PET scans. In particular, potential blood biomarkers for Alzheimer's disease include:

• Aβ_1-42
• t-Tau
• p-Tau₁₈₁

Blood Biomarkers for Neurodegeneration

In addition to blood biomarkers for Alzheimer’s disease, researchers have also uncovered potential blood biomarkers for neurodegeneration that may provide additional information on disease progression and therapeutic response. These include:

• Neurofilament light chain (NfL): Neurofilament is an axonal cytoskeletal protein found only in neurons. Of the four subunits (light, medium, heavy, and alpha-internexin), NfL is the most abundant. In neurodegenerative diseases, including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and multiple sclerosis, NfL levels in CSF are often elevated. Several studies have reported that NfL levels in blood correlate with those in CSF.
• Glial fibrillary acidic protein (GFAP): GFAP is a type III intermediate filament protein found in astrocytes in the brain. When astrocytes are damaged, they release GFAP into bodily fluids such as CSF and blood. Several studies have found that GFAP expression correlates with amyloid-beta plaque density in Alzheimer’s disease brain tissue. 

The Future Role of Blood Biomarkers for Alzheimer’s Disease in Clinical Trials

Clinical trials are fundamental to our ability to advance Alzheimer's disease research, assess the safety and efficacy of promising new strategies for Alzheimer's disease treatment, and bring effective therapies to market. As the number of individuals living with Alzheimer's disease continues to grow at a rapid pace, Alzheimer’s disease clinical trials are more important than ever. 

While the potential of emerging drugs and therapies for Alzheimer’s disease progresses rapidly, diagnostics tools and methods for robust monitoring of neurocognitive function for clinical trials remain rather outdated, driving subject recruitment costs through the roof, prolonging trial timelines, and contributing to clinical trial failures. 

New, novel diagnostic and monitoring approaches, including blood biomarkers for Alzheimer’s disease, will likely be an integral aspect needed to increase the cost efficiency, speed, and success of Alzheimer’s disease clinical trials. While blood-based biomarker tests for Alzheimer’s disease are currently very expensive and difficult to access, they may in the future:

• Serve as an initial tool to narrow down the subject pool, filtering out ineligible subjects, prior to completing imaging or diagnostic procedures necessary for key inclusion criteria.
• Be utilized as a robust proxy to traditional endpoints, providing greater insight into therapeutic response and drug efficacy.