Major advances have been made in the development of Alzheimer’s disease (AD) biomarkers in the last two decades, with models of the temporal evolution of AD biomarkers offering the possibility of staging the course of the disease. Despite the achievements in this field, a major unmet need is the standardization of quantitative metrics for AD imaging biomarkers, according to an article published in the May issue of Radiology.

“Although the value of imaging biomarkers in both clinical diagnosis and clinical trials is clear, major barriers exist to actual implementation,” wrote Clifford R. Jack, Jr., MD, of the department of radiology at the Mayo Clinic in Rochester, Minn.

AD, once not considered a great public health concern, is now recognized as a “potentially unprecedented public health problem,” according to Jack, with the aging of the population drawing more attention to the disease. Current estimates peg the number of people with AD in the U.S. at 5.3 million, the vast majority of whom are over 65 years old. The incidence of AD doubles every five years after the age of 60.

Fortunately, understanding of AD biomarkers has increased alongside the concern, and there are five well-established biomarkers which can be divided into two mechanistic categories:

• Measures of brain amyloid-beta peptide deposits (either cerebrospinal fluid amyloid-beta 42 or amyloid PET imaging)
• Measures of neuronal injury and degeneration (cerebrospinal fluid tau, FDG PET, or structural MRI)

“On the basis of the observations that AD biomarkers provide information about different AD-related pathophysiologic processes and the idea that these processes may be temporally ordered, great interest has arisen recently in the idea of staging disease by using biomarkers,” wrote Jack.

These recent hypothetical models of AD biomarker evolution are based on the idea that AD biomarkers develop abnormally but in a sequential manner, according to Jack. Amyloid biomarkers depart from normal 15 years or more before clinical symptoms appear, while the neuronal injury and degeneration biomarkers depart later, but correlate better with concurrent clinical symptoms.

Even with these developments, imaging AD biomarkers do not currently play a prominent role in daily clinical practice, likely due to the lack of therapies, wrote Jack. Early diagnosis does little good if there are no disease-modifying treatments to administer. Early diagnostic guidelines contained no mention of imaging biomarkers, but recently updated diagnostic guidelines for AD, organized by the National Institute on Aging, suggest the use of biomarkers to establish the presence of AD.

One major hurdle remains in the use of AD biomarkers: a lack of standardization of imaging measurements. Verbal descriptions of a visual assessment of atrophy or hypometabolism don’t lend themselves to reliably tracking the incremental stages of atrophy or glucose uptake, according to Jack. Work has been done in the area of developing quantitative measurements, particularly for MRI, but universal standards have not been developed.

“An important contribution that the imaging community could make would be to establish open-source methods for standardized quantification,” wrote Jack. “If imaging is to take its place as a widely used, clinically relevant disease biomarker for AD, then imaging should transform itself to operate as do biomarkers in other fields.”

Unlike measures of blood pressure or serum lipids, quantitative metrics for AD biomarkers have not been developed, limiting the diagnostic usefulness of imaging. “This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials.”