Neurology

Alzheimer's Disease

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Biomarkers in Alzheimer’s Disease

clinical topic updates by Vijay K. Ramanan, MD, PhD
Overview

While imaging and cerebrospinal fluid (CSF) biomarkers have long been used in the management of Alzheimer’s disease (AD), blood-based biomarkers (BBBs) have most recently emerged as a promising tool, with several advances made in recent years. These biomarkers have potential applications in the screening, diagnosis, treatment, and monitoring of patients with AD.

“The ability to pair a standard evaluation with biomarker testing, which positively assesses for biological signs of the underlying disease pathophysiology, can be really helpful in increasing diagnostic confidence.”
— Vijay K. Ramanan, MD, PhD

Anytime someone is suspected of having a neurologic disease, it is important to be as confident as possible about the diagnosis, particularly when you are talking about a potentially devastating disease such as AD. There is a lot at stake for patients with AD and for all of us who are helping to support their care. There are tests that are considered standard components of the evaluation to help rule out mimics, particularly potentially treatable or modifiable conditions with symptoms that mimic the cognitive issues seen in AD. The ability to pair a standard evaluation with biomarker testing, which positively assesses for biological signs of the underlying disease pathophysiology, can be really helpful in increasing diagnostic confidence.

 

We have imaging biomarkers, including magnetic resonance imaging (MRI) scans, that can show atrophy or loss of tissue caliber in areas of the brain that tend to be susceptible to the disease. While not wholly specific for AD in isolation, these MRI findings can be helpful clues to diagnosis. In addition, fluorodeoxyglucose positron emission tomography (PET) scans may identify hypometabolism, which is an indicator of degeneration and dysfunction in characteristic areas of the brain involved in AD. Additionally, other types of PET scans, particularly amyloid and tau PET scans, can provide biomarker evidence that patients have amyloid plaques or tau tangles building up in parts of their brains affected by the disease. However, not every facility or center is going to have uniform access to these tests or expertise to interpret them.

 

For many years, we have had CSF biomarkers that can also assess for the pathophysiologic changes of AD. However, a lumbar puncture is required to collect fluid samples for biomarker testing. Although generally safe, this is a technically invasive procedure that requires expertise to perform.

 

While not perfect, BBBs have a number of advantages as complements to imaging and CSF biomarkers. Since most patients with cognitive symptoms are getting at least initial care in primary care and general neurology settings, BBBs can play a role in screening and early evaluation in those environments. Blood draws are widely accessible in the community, are not invasive, and do not require specialty scanners, tracers, or neuroradiology expertise compared with imaging and CSF biomarkers. Some of the challenges associated with the use of BBBs simply relate to the fact that these assays are still relatively new, with a lot of ongoing developments through research. I think that we will get much more information as these BBBs are more widely used in real-world clinical practice.

 

There are many different molecules that have been proposed as relevant in AD. Most experts in the field currently consider phosphorylated tau (p-tau) species, principally p-tau217, to be the best indicator for the presence of AD pathophysiology, with the specific readout being that, in the right context, individuals with elevations in p-tau217 are likely to be amyloid β positive on PET. Additional biomarkers are being evaluated that may be more specific for the tau tangles that we see in AD, and still other biomarkers could comment on other aspects of disease pathophysiology, such as neurodegeneration or immune activation.

 

As we look to the future, is it possible that we may have therapies that could act on AD pathophysiology before an individual develops symptoms to potentially delay or even prevent the onset of cognitive difficulties later on? In that possible future, one could see biomarker testing being deployed early to identify those individuals who may benefit from these types of preventive therapies. Ongoing studies will help us define those details over the coming years, but it is not difficult to see the possibilities and to look at them with a very positive lens.

References

Ankeny SE, Bacci JR, Decourt B, Sabbagh MN, Mielke MM. Navigating the landscape of plasma biomarkers in Alzheimer’s disease: focus on past, present, and future clinical applications. Neurol Ther. 2024;13(6):1541-1557. doi:10.1007/s40120-024-00658-x

 

Ashton NJ, Brum WS, Di Molfetta G, et al. Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for Alzheimer disease pathology. JAMA Neurol. 2024;81(3):255-263. doi:10.1001/jamaneurol.2023.5319

 

Dubois B, von Arnim CAF, Burnie N, Bozeat S, Cummings J. Biomarkers in Alzheimer’s disease: role in early and differential diagnosis and recognition of atypical variants. Alzheimers Res Ther. 2023;15(1):175. doi:10.1186/s13195-023-01314-6

 

Graff-Radford J, Yong KXX, Apostolova LG, et al. New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol. 2021;20(3):222-234. doi:10.1016/S1474-4422(20)30440-3

 

Hampel H, Hu Y, Cummings J, et al. Blood-based biomarkers for Alzheimer’s disease: current state and future use in a transformed global healthcare landscape. Neuron. 2023;111(18):2781-2799. doi:10.1016/j.neuron.2023.05.017

Vijay K. Ramanan, MD, PhD

    Consultant, Division of Cognitive/Behavioral Neurology
    Director, Alzheimer's Disease Treatment Clinic
    Assistant Professor
    Department of Neurology
    Mayo Clinic
    Rochester, MN
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