Biomarkers for Alzheimer’s Disease

By Mariella Careaga

enfermedad de Alzheimer is a degenerative brain disorder that progressively impacts a person’s cognitive functioning and behavioral capacities, leading, ultimately, to the disruption of that person’s daily life. In the past, doctors could only make a definitive Alzheimer’s diagnosis by directly examining the patient’s brain tissue in a post-mortem autopsy. But, thanks to researchers, a lot has changed. Now, physicians have growing access to tests that help see measurable indicators, known as biomarkers, related to enfermedad de Alzheimer and other forms of dementia in a living person.

It is estimated that more than 55 million people around the world live with dementia…

enfermedad de Alzheimer, abbreviated as AD, is commonly diagnosed in old age and may account for 60% to 70% of total dementia cases (World Health Organization, 2021). Dementia is an umbrella term for a particular set of symptoms that includes memory, thinking, and language difficulties. It is estimated that more than 55 million people around the world live with dementia, and nearly 10 million new cases are added every year, pressing scientists to not only understand the causes of dementia but also to develop therapies to treat it.

Many of us know AD for the severity of its symptoms, but that does not define the disease according to Suzanne E. Schindler, associate professor of neurology at Washington University School of Medicine. “enfermedad de Alzheimer is defined by specific abnormalities in the brain including amyloid plaques and neurofibrillary tangles,” says Schindler. The beta-amyloid protein clumps accumulate outside neurons whereas neurofibrillary tangles, made of a protein called tau, are found inside neurons. These abnormal changes in brain proteins, first observed by Alois Alzheimer more than 100 years ago, are hallmarks of AD and are thought to contribute to neuronal loss seen in the disease. Over the last decades, AD diagnosis and research has changed significantly as scientists have developed ways to measure beta-amyloid and tau proteins in living patients.

The Biomarker Revolution
Biomarkers, a short name for “biological markers”, are quantifiable indicators of normal and abnormal processes that we can detect in samples from bodily fluids, tissues, and organs. Physicians and researchers can use them to monitor normal bodily functions, diagnose health conditions, monitor the body’s response to treatment, and identify people at a greater risk for developing a disease.

In the quest for AD biomarkers, scientists first turned their attention to the cerebrospinal fluid (CSF), a clear and watery liquid that flows in and around the brain and spinal cord. Because CSF is in constant contact with the brain, proteins and other substances made by brain cells can be measured in the fluid to aid the diagnosis of neurological problems. Beta-amyloid and tau proteins are found in the CSF, and changes in their levels hint at changes in these proteins in the brain. For example, the reduction of a specific beta-amyloid protein called beta-amyloid 42 in the CSF is associated with an increase in amyloid plaques in the brain, as more amyloid proteins clump together in that organ (Jack and Holtzman, 2013; Visser et al., 2009). Regarding tau, an increase in tau (or in its phosphorylated version) in the CSF is also associated with more neurofibrillary tangles in the brain (Jack and Holtzman, 2013). CSF biomarkers are commonly used in research, but the recent approval of a CSF test for AD by the Food and Drug Administration (FDA) might enable broad use of CSF tests in clinical settings.

Different types of brain scans, including computed tomography (CT), magnetic resonance imaging (resonancia magnética), and positron emission tomography (TEP), have also been used to diagnose AD or other forms of dementia. CT scans and MRIs are imaging techniques that show the size and shape of the brain. These images might reveal, for example, that regions of a person’s brain are smaller than they should be, which could suggest that brain atrophy is taking place (Johnson et al., 2012). Such a result, along with other clinical tests, might help determine if that person has dementia.

Unlike MRIs and CT scans, TEP scans allow us to see how tissues in the body are working. To do that, small quantities of a radioactive substance, called a tracer, are injected into a person’s bloodstream and can reveal both normal and abnormal metabolic changes. In the brain, for example, a tracer made of a radioactive atom and a molecule similar to glucose can be used to measure how our brain cells are producing energy to fuel their physiological processes. Some specific tracers can also identify amyloid plaques and abnormal tau protein accumulation by binding to these protein deposits in the brain (Zetterberg & Bendlin, 2021). To date, one tau and three amyloid TEP scans are approved by the FDA for AD diagnosis and research.

…beta-amyloid and tau proteins can also be detected in the blood…

More recently, studies have shown that beta-amyloid and tau proteins can also be detected in the blood, and levels of these proteins can serve as biomarkers since they correlate with levels in the CSF and brain (Mielke et al., 2018; Teunissen et al., 2022). “Blood-based biomarkers are advantageous over a lumbar puncture for the collection of CSF or neuroimágenes in terms of cost, invasiveness, feasibility, and access,” says Michelle Marie Mielke, PhD, chair of the department of Epidemiology and Prevention and professor of Epidemiology and Gerontology at the Wake Forest University School of Medicine. In the US, the majority of people are diagnosed and treated for AD in primary care, where there are not enough neurologists and geriatricians, says Mielke. Thus, “there is a need for less invasive tests” that can narrow down whether the cause of cognitive difficulties is related to AD.

Why do AD biomarkers matter?
The use of AD biomarkers can significantly impact a patient’s life. In a recent study, researchers assessed the impact of taking an amyloid TEP scan on the clinical management of patients with mild cognitive impairment (MCI) or dementia of unknown cause. When amyloid TEP scan results were available, clinicians diagnosed more accurately those with or without AD, felt more confident about their diagnosis, and changed the use of drugs to treat AD symptoms in more than 40% of the patients (Rabinovici et al., 2019). Additionally, including biomarkers in the clinical practice is likely to reduce AD misdiagnosis or underdiagnosis, which is still common (Rabinovici et al., 2019).

…including biomarkers in the clinical practice is likely to reduce AD misdiagnosis or underdiagnosis…

In AD research, biomarkers can be used to identify patients with AD brain abnormalities years before the first signs of memory and thinking difficulties show up, says Schindler. These cognitively normal patients can then be enrolled in studies known as preventive clinical trials, in which researchers test whether specific treatments prevent or slow down the onset of dementia symptoms.

Although biomarkers have helped AD diagnosis and research, there are still limitations. According to Schindler, we still do not know how individual factors such as age, sex, and additional medical conditions might impact these biomarkers. For example, in a recent study, researchers showed that some medical conditions such as kidney disease affect tau protein levels measured in the blood (Mielke et al., 2022). Knowing how other diseases alter AD biomarkers is especially important as most patients affected by AD are “older adults who have multiple comorbidities,” says Mielke.

Over the last decades, advances in AD biomarkers have led to exciting new findings. Today, researchers and physicians can see AD-related alterations in living people, something not possible a few decades ago. These AD biomarkers can be used to diagnose patients, enroll the right participants in clinical trials, and track the participants’ response to potential new drugs. As AD biomarker research moves forward, improvements on the currently available biomarkers, along with the development of techniques that measure AD-related abnormalities in other organs (Hart et al., 2016), will likely provide more tools to patients so they can plan for the future and start treating their symptoms as early as possible.

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Escrito por Mariella Careaga
Imagen por Sumana Shrestha
Edited by Lauren Wagner, Mary Bullock, and James Cole

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Referencias
Hart, N. J., Koronyo, Y., Black, K. L., & Koronyo-Hamaoui, M. (2016). Ocular indicators of Alzheimer’s: exploring disease in the retina. Acta neuropathologica, 132(6), 767–787. https://doi.org/10.1007/s00401-016-1613-6

Jack, C. R., Jr, & Holtzman, D. M. (2013). Biomarker modeling of enfermedad de Alzheimer. Neurona, 80(6), 1347–1358. https://doi.org/10.1016/j.neuron.2013.12.003

Johnson, K. A., Fox, N. C., Sperling, R. A., & Klunk, W. E. (2012). Brain imaging in Alzheimer disease. Cold Spring Harbor perspectives in medicine, 2(4), a006213. https://doi.org/10.1101/cshperspect.a006213

Mielke, M. M., Hagen, C. E., Xu, J., Chai, X., Vemuri, P., Lowe, V. J., Airey, D. C., Knopman, D. S., Roberts, R. O., Machulda, M. M., Jack, C. R., Jr, Petersen, R. C., & Dage, J. L. (2018). Plasma phospho-tau181 increases with enfermedad de Alzheimer clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimer’s & dementia : the journal of the Alzheimer’s Association, 14(8), 989–997. https://doi.org/10.1016/j.jalz.2018.02.013

Mielke, M. M., Dage, J. L., Frank, R. D., Algeciras-Schimnich, A., Knopman, D. S., Lowe, V. J., Bu, G., Vemuri, P., Graff-Radford, J., Jack, C. R., Jr, & Petersen, R. C. (2022). Performance of plasma phosphorylated tau 181 and 217 in the community. Nature medicine, 28(7), 1398–1405. https://doi.org/10.1038/s41591-022-01822-2

Rabinovici, G. D., Gatsonis, C., Apgar, C., Chaudhary, K., Gareen, I., Hanna, L., … & Carrillo, M. C. (2019). Association of amyloid positron emission tomography with subsequent change in clinical management among medicare beneficiaries with mild cognitive impairment or dementia. Jama, 321(13), 1286-1294. https://doi:10.1001/jama.2019.2000

Schindler, S. E., & Bateman, R. J. (2021). Combining blood-based biomarkers to predict risk for enfermedad de Alzheimer dementia. Nature Aging, 1(1), 26-28. https://doi.org/10.1038/s43587-020-00008-0

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World Health Organization. (2021). Dementia. World Health Organization. Retrieved August 10, 2022, from https://www.who.int/news-room/fact-sheets/detail/dementia

Zetterberg, H., & Bendlin, B. B. (2021). Biomarkers for enfermedad de Alzheimer-preparing for a new era of disease-modifying therapies. Molecular psychiatry, 26(1), 296–308. https://doi.org/10.1038/s41380-020-0721-9

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Mariella Careaga

Mariella received her degree in Biomedicine from Universidade Federal de São Paulo (UNIFESP), in Brazil. Then, she was a grad student at the Psychobiology department at UNIFESP, where she earned her master’s and Ph.D. degrees. As a grad student, she was mostly interested in the effects of stress (or stressful situations) on behavior and fear memory. Currently, she is a postdoc at Uniformed Services University of the Health Science, and she also participates in science communication initiatives in Brazil (Nunca vi um cientista and Eureka!Brasil), in which she writes articles about science-related topics.

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