Alzheimer's Biomarker in the Cerebrospinal Fluid and Plasma

A reliable biomarker is important in diagnosing and treating patients with Alzheimer’s Disease (AD). A good Alzheimer’s biomarker allows for early identification and therapy. Early identification can help a patient adapt to lifestyle changes, and early treatment has many benefits for the patient and the field of AD research. Another important part of finding a reliable biomarker is to differentiate between AD and other types of dementia. AD accounts for 60%-70% of all dementia cases.¹ There are a number of methods available allowing for AD diagnosis, and the most reliable method of identifying AD is post-mortem brain analysis, which is not an option for a patient living with AD.² Other ways to find Alzheimer biomarkers lie in the cerebrospinal fluid (CSF) and blood. An Alzheimer’s biomarker must also be specific, allowing for differentiation from other neurological diseases, including multiple types of dementia. Currently, a doctor can diagnose AD in a living patient using information gathered from family history, physical evaluation, neuroimaging, and blood tests.

Three Alzheimer’s biomarkers identified in the CSF are both specific (>95%) and sensitive (>85%) as diagnostics.³ Beta amyloid (1-42) (AB) plaque deposits are a hallmark of AD. AB(1-42) is a 42 amino acid peptide produced during the cleavage of amyloid precursor protein (APP). AB can aggregate in the brain, causing plaques in multiple instances, such as acidosis or metals. Decreased levels of AB(1-42) compared to AB(1-37) or AB(1-40) is specific for Alzheimer’s disease, and the two shorter peptides are important in the diagnosis of dementia. Low levels of AB(1-42) may occur because it is not easily cleared from the brain to the CSF. A second important Alzheimer’s biomarker is total tau which is a microtubule associated protein. Tau is known to increase as a person ages; however, levels of total tau in AD patients are 200%-300% higher compared to persons in the same age group.⁴ Interestingly, the prion disease, Creutzfeldt-Jacobs, has even higher levels of total tau than people with AD (>3000 pg/mL vs. >600 pg/mL). The third major Alzheimer’s biomarker in CSF is phosphorylated tau. Total tau can be phosphorylated in nearly 40 sites in people with AD. Specifically, at amino acid 181, tau is more likely to be phosporylated compared to healthy controls.

Plasma biomarkers are of great interest for Alzheimer’s research. Finding plasma Alzheimer’s biomarkers presents more of a challenge when compared to CSF biomarkers as some proteins may not pass through the blood-brain barrier. Current AD blood biomarkers of interest are involved in inflammation, senescence, apoptosis, and cerebrovascular dysfunctions. AB-related proteins and enzymes related to tau pathology are potential plasma biomarkers of AD. AB(1-42) levels, however, are often unstable in blood compared to CSF, and tau-related biomarkers have not yet been found to be useful in the circulating blood. A recent study has shown that a panel of 18 inflammatory proteins may act as Alzheimer’s biomarkers in blood.⁵ These markers include a combination of chemokines, cytokines, growth factors, and binding proteins. These are only an example of the vast amount of research going on to find more blood biomarkers for AD.

The future of AD diagnostics and biomarkers will most likely involve a panel of proteins. This panel will allow for early detection, immediate treatment, and helpful therapy for many Alzheimer’s patients. While research is ongoing to find reliable and reproducible results in blood samples, CSF samples are already showing potential for the future of Alzheimer’s patients.