Alzheimer’s disease (AD) is one of the most prevalent illnesses in the U.S. One in three seniors die due to AD or another dementia, making it the sixth leading cause of death nationally. (1) There are no clinically proven therapies to treat AD. Diagnosis has historically been based on clinical presentation, but novel research into fluid biomarkers implicated in AD pathology may allow for earlier and more specialized diagnoses. (2

Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood are likely the future of AD diagnosis, research, and treatment. The ability to track AD progression using such biomarkers would allow researchers to determine the effects of certain therapeutics, find preventative treatments, and allow for diagnosis earlier in the disease progression. (2,3) The most common neurological changes associated with AD pathology are amyloid-β (Aβ) plaque formation and neurofibrillary tangles made up of tau protein. (3) Identifying biomarkers that reflect these changes is the goal of AD fluid biomarker research.

The ratios between t-tau to Aβ42 and p-tau to Aβ42 are clinically recognized biomarkers of AD, with a multitude of studies confirming their specificity. (2) The difference between t-tau and p-tau is the identity of the phosphorylated amino acids, but both are implicated in AD. (4) Most amyloid plaques in the brain are made up of Aβ42. (3) By examining the ratio of phosphorylated tau protein to Aβ42, researchers can determine the amyloidosis of the brain which reflects AD pathology. (2

Novel AD biomarkers including BACE1 and hFABP have been the subject of recent research. BACE1 is a major protease for cell surface proteolysis, and CSF BASE1 has been reported to be higher in AD patients compared to controls. BASE1 has also been shown to be higher in patients with mild cognitive impairment (MCI) who then progressed to AD, when compared to stable MCI patients. (2) hFABP is an acid-binding protein that has been associated with CSF Aβ42, but not with cognitive impairment. CSF hFABP has been shown to predict progression from MCI to AD and to help differentiate AD from Parkinson’s or dementia with Lewy bodies. (2) Although the number of studies about BACE1 and hFABP is limited, it is growing. Interest in finding novel AD biomarkers has skyrocketed as the American medical system continues to bear the burden of AD patients, and the need for research and therapies grows each year. 

Another diagnostic tool being developed to facilitate early AD diagnosis is Esurgi’s eyeAD which is both non-invasive and accessible. It is a real-time adult diagnostic tool that takes proven biomarkers out of the lab and into the community, including patients’ homes, leading to early diagnosis. The eyeAD tracks eye movements in real-time in order to diagnose AD. A growing body of research has shown that AD patients experience changes to fundamental eye movements such as smooth pursuit motion and scene exploration. (5) Using this knowledge can be vital for developing better diagnostic tools such as the eyeAD. In combination with fluid biomarkers, the eyeAD can help diagnose AD as well as test novel research techniques and therapies. 

Sources:

1. Alzheimer’s Association, (2020). Facts and Figures. Retrieved January 14, 2021, https://www.alz.org/alzheimers-dementia/facts-figures.

2. Shaw, L. M., Arias, J., Blennow, K., Galasko, D., Molinuevo, J. L., Salloway, S., . . . Fifer, S. (2018). Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease. Alzheimer’s & Dementia, 14(11), 1505-1521.

3. Molinuevo, J. L., Ayton, S., Batrla, R., Bednar, M. M., Bittner, T., Cummings, J., . . . Blennow, K. (2018). Current state of Alzheimer’s fluid biomarkers. Acta Neuropathologica, 136(6), 821-853. 

4. Hampel, H., Blennow, K., Shaw, L. M., Hoessler, Y. C., Zetterberg, H., & Trojanowski, J. Q. (2010). Total and phosphorylated tau protein as biological markers of Alzheimer’s disease. Experimental Gerontology, 45(1), 30-40.

5. Molitor, R. J., Ko, P. C., & Ally, B. A. (2015). Eye movements in Alzheimer’s disease. Journal of Alzheimer’s disease : JAD, 44(1), 1–12.

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