Biomarker Research

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When effective treatments for Alzheimer’s and related dementias become available, doctors will need reliable tests for early detection and diagnosis. To this end, NIH invests in the development of easier-to-use, less expensive testing methods. This investment led to significant advances in 2020, particularly in the further development of blood and imaging tests. For example:

Since fall 2020, physicians in a clinical research practice can order blood tests for amyloid protein, a hallmark sign of Alzheimer’s, for any patients, even those who are not participating in a study.
Advances were made in brain imaging, most notably, the FDA approval of the first PET scan product to detect tau tangles in the brain, another hallmark sign of Alzheimer’s.

However, the current ability to obtain a diagnostic test for Alzheimer’s and related dementias in a doctor’s office is still quite limited, and biomarker imaging and lab tests are mainly used today by researchers to study people who volunteer to take part in related studies. NIH continues to fund multiple studies to discover and validate additional testing options.

Researchers recently identified various proteins and other substances that have potential to be new biomarkers of Alzheimer’s and related dementias:

Tau tangles: When tau tangles collect in the brain, various tau forms can also be found in the spinal fluid and blood. Two NIH-supported research teams devised and tested methods of measuring ptau217 in blood samples. Both teams reported that ptau217 was better than ptau181 at detecting signs of Alzheimer’s and that ptau217 had the potential to rival PET imaging and spinal fluid testing at Alzheimer’s detection. Researchers continue to further develop blood test methods that detect ptau217.
Protein groups: Researchers supported by the NIH Accelerating Medicines Partnership^® Program for Alzheimer’s Disease (AMP^® AD) measured 3,500 proteins in spinal fluid and 12,000 proteins in brain samples from people with Alzheimer’s and from cognitively normal study participants. The research team identified groups of proteins associated with Alzheimer’s, findings that are significant toward the discovery of new fluid biomarkers for Alzheimer’s.
Neurofilament light chain: A team of researchers funded in part by NIH found further evidence to support the development of a blood-based biomarker test for neurofilament light chain for the inherited form of Alzheimer’s.

More research is needed to better understand whether neurofilament light chain would be a useful biomarker for people with the more common form of Alzheimer’s disease, meaning the type that is not inherited.

Lipids: A team of international researchers analyzed the entire set of lipids (fatty substances) in blood plasma samples from about 2,000 people, including participants in the NIA-supported Alzheimer’s Disease Neuroimaging Initiative. The team discovered that certain lipids are linked to Alzheimer’s, signifying that these substances have potential as fluid biomarkers.

Recent studies have also noted that people with Alzheimer’s may have changes with their eyes or vision and that they may experience sleep disturbances, which are two more avenues of study for biomarkers:

Eyes and vision changes: Recent NIH-supported studies have suggested that retina changes and vision and pupil changes might serve as biomarkers of Alzheimer’s and related dementias.
Sleep disturbance: Three recent studies explored the relationship between sleep deprivation and abnormal deposits of certain proteins, such as tau tangles and amyloid plaques.

One of the research teams suggested that measuring sleep activity with wearable devices may have potential as an easy and safe way to predict the abnormal accumulation of proteins in the brain before cognitive decline and other symptoms of brain disease develop.

Science Spotlight: FDA approves first diagnostic agent for tau tangles

In 2020, FDA approved flortaucipir, the first diagnostic agent for measuring tau tangles on a PET scan of the brain. This approval is a major technological advance in biomarker tests for Alzheimer’s.

The radioactive diagnostic agent flortaucipir binds to dense areas of tau tangles, which appear bright red on a PET brain scan. An NIA-funded project demonstrated a high degree of similarity between the amount and location of tau tangles detected with the brain scan while research participants were alive and in an examination of brain tissue after death.

Before FDA approval of flortaucipir, determining the distribution and density of tau tangles in the brain was possible only through autopsy. The new diagnostic agent fills an important missing piece of the diagnostic puzzle.

Results from a tau PET scan, when combined with results from an amyloid PET scan, can help doctors evaluate a person who has cognitive impairment.

Previously, FDA approved three PET scan diagnostic agents for detecting amyloid plaques in people who have Alzheimer’s.

Developing biomarkers for Parkinson’s disease dementia and dementia with Lewy bodies

Biomarker development goes beyond Alzheimer’s: Many NIH-supported projects are aimed at finding new biomarkers and developing diagnostic tests for Alzheimer’s-related dementias, such as Parkinson’s disease dementia and dementia with Lewy bodies.

For example, clumped forms of the alpha-synuclein protein are found in the brains of people with Parkinson’s disease and Lewy body dementias, and a test of spinal fluid can detect the protein.

To develop a diagnostic that would be easier than the spinal fluid test, NIH-supported researchers are working on a skin test for this biomarker. The team reported that they detected deposits of the clumped protein in skin samples from people with Lewy body dementias but not in healthy people. The skin test results were comparable to spinal fluid tests for alpha-synuclein.
To further our understanding of potential biomarkers for Parkinson’s and other Lewy body dementias, NIH has been supporting several projects and programs, including the Accelerating Medicines Partnership® Program for Parkinson’s Disease (AMP® PD).
NIH released a new funding opportunity to support the identification of biomarkers for Lewy body dementia. The aim is research projects that will increase understanding of how clinical information from people with Lewy bodies corresponds with abnormal areas observed in brain tissue collected after death.

Program Spotlight: Alzheimer’s Biomarkers Consortium — Down Syndrome

People living with Down syndrome are at high risk of developing Alzheimer’s. By about age 40, nearly all adults with Down syndrome have a hallmark sign of Alzheimer’s: amyloid plaques in their brain. Experts estimate that at least 50% of people with Down syndrome will develop Alzheimer’s dementia as they age.

NIH is funding Alzheimer’s Biomarkers Consortium — Down Syndrome (ABC-DS), a multi-institution research team led by the University of Pittsburgh, to expand research on the biomarkers of Alzheimer’s in adults with Down syndrome.

The increased risk of Alzheimer’s in this population may stem from the fact that people with Down syndrome have three rather than two copies of a key gene that produces amyloid. By learning the biological mechanism that explains the increased risk, researchers may devise methods of prevention and treatment not just for those with Down syndrome, but also for other adults at risk of developing Alzheimer’s.

A recent analysis of data from the NIH-supported ABC-DS study suggests that people with Down syndrome show similar changes in metabolic processes as people with late-stage Alzheimer’s. The same pattern of metabolic changes occurs for people with Down syndrome who go on to develop Alzheimer’s and people with late-stage Alzheimer’s. The findings suggest that measures of metabolic substances may have potential as blood-based biomarker tests.

Launched in 2018, the NIH INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is a related research initiative for individuals with Down syndrome. Because one of the conditions of special interest for the INCLUDE Project is Alzheimer’s, it supports the Alzheimer’s Biomarkers Consortium — Down Syndrome.

New initiative to address health disparities through biomarker research

To better understand the prevalence, progression, and clinical impact of Alzheimer’s among Mexican Americans, NIH awarded additional funding in 2020 for more PET scans and other biomarker measures to the ongoing Health and Aging Brain Among Latino Elders (HABLE) study.

The additional funding will support the Health and Aging Brain Among Latino Elders-Amyloid, Tau, and Neurodegeneration (HABLE-AT[N]) study, which enables researchers to collect amyloid and tau PET imaging and other biomarker measures.

The goal is to better understand health disparities of brain aging and Alzheimer’s between Mexican Americans and non-Latino whites. An additional benefit of HABLE and HABLE AT(N) will be the ability to better classify/categorize participants into groups by type of dementia and stage of the disease. This will help facilitate potential enrollment in future studies.

Science Spotlight: First blood test of amyloid, a biomarker for Alzheimer’s, now available to doctors

Thanks in part to NIH funding, researchers at C₂N Diagnostics developed the PrecivityAD™ blood test. This is the first amyloid blood test to become available to some doctors, who can send blood samples to C₂N’s lab to analyze blood for amyloid. While this test does not technically diagnose Alzheimer’s, it can help doctors evaluate their patients with cognitive disorders.

C₂N’s lab measures the concentrations of amyloid 42 and 40 and checks for the presence of apolipoprotein E. From these measures, C₂N’s automated method generates an Amyloid Probability Score to suggest the likelihood of amyloid plaques in the brain. A high score is consistent with a high level of amyloid plaques found on a PET scan.

Although C₂N has demonstrated that their lab provides accurate and reliable test results for blood samples, studies are needed to further evaluate this method with people who have symptoms of Alzheimer’s, including diverse populations.

Creating a legacy through brain donation

To help encourage the public to take part in brain donation for ongoing research efforts, NIH developed and released a feature article and social media toolkit. These materials are designed to be shared broadly and to spark discussions about this important topic.

The article focuses on why brain donors are needed and explains the steps in developing a donation plan. The social media toolkit includes image cards, sample social media posts, a flyer, an infographic, and drop-in language for grantee and other newsletters.

Available in both English and Spanish, the toolkit is already being used by the NIA-supported Alzheimer’s Disease Research Centers and others to spread the word about the importance of brain donation.

These brain donation materials also explain how people can enroll to donate to the NIH NeuroBioBank, which is supported by several parts of NIH:

Through its NeuroBioBank, NIH distributes thousands of samples of human brain tissue to the research community each year to help spur research progress in understanding dementia. Many more donors are needed, however, because progress in understanding dementia relies on donors who represent the diversity of the U.S. Learn more about the donation process.

Program Spotlight: What is the role of white matter lesions in cognitive impairment and dementia?

In October 2020, University of California, Davis (UC Davis), received NIH funding for a new project called White Matter Lesion Etiology of Dementia in Diverse Populations (Diverse VCID). The project, which is part of NIH’s Vascular Contributions to Cognitive Impairment and Dementia (VCID) program, is studying health disparities in diverse racial and ethnic populations.

Abnormally bright white areas on brain images — also known as white matter lesions or white matter hyperintensities — indicate injury. They are very common and can occur from a stroke, normal aging, or other causes. Researchers have linked having high levels of the bright white areas to dementia. The UC Davis project will analyze both age-related and disease-related white matter lesions for their possible link to dementia.

This will be the first large study of a diverse population on the long-term effects of white matter lesions on thinking and dementia risk. By recruiting participants who represent the diversity of the U.S. population, the scientists leading the project aim to lay the groundwork for creating reliable standards for assessing, diagnosing, and treating people with cognitive problems and white matter lesions.

By analyzing MRI scans and other measures, the research team will study the role of vascular factors, particularly white matter lesions, in cognitive impairment and dementia. The project will identify whether white matter lesions differ by race, ethnicity, and sex.

Recruitment of participants is expected to begin in late 2021 at UC Davis and at least 10 other locations throughout the United States.

This project supports 27 investigators at 12 institutions, and it will leverage resources from the NIH-funded MarkVCID initiative, through which researchers have developed and validated several VCID biomarker kits.

Behavioral research and biomarkers

Researchers have begun to investigate the possible psychological effects on people who do not have symptoms of dementia but who are told they have a biological sign of Alzheimer’s.

Two independent teams of behavioral and social scientists recently reported that learning biomarker test results does not cause serious distress among Alzheimer’s research participants. However, further research with more diverse populations is needed to examine the short-term and lasting psychological effects. More research is also needed on how physicians can best communicate results to lessen the chance of serious distress.

Studies on other possible effects from biomarker tests in people without symptoms are also being conducted. In June 2021, the National Academies of Sciences, Engineering, and Medicine hosted an NIA-sponsored two-day workshop to advance additional dialogue around this issue, explore new ideas, and discuss possible solutions to challenges arising from the use of biomarker tests.

Investing in the Future: Research Trainee Udell Holmes III

Providing funding for research training is one way that NIH nurtures the next generation of scientists.

At Columbia University, investigators recruit students from underrepresented groups to conduct research projects with neuroimaging data for their NIA-funded Summer of Translational Aging Research for Undergraduates (STAR U). The trainees are helping to develop brain images as biomarkers of dementia through NIA’s Advancing Diversity in Aging Research (ADAR) through Undergraduate Education program. Udell Holmes

An example of a STAR U trainee is Udell Holmes III, who in 2020 earned a bachelor of arts degree in psychology with honors from Cleveland State University. Holmes conducted an independent research project studying the default mode network, a group of areas in the brain that is active when an individual is not focused on the outside world. Neuroscientists study the default mode network with imaging methods such as brain MRI.

Holmes set out to determine whether the default mode network can be developed as a biomarker for detecting subjective cognitive decline. Subjective decline is an individual’s perception that their memory or thinking skills are worse than for other people their age, but standard diagnostic tests do not detect any difference. Researchers have wondered whether subjective decline may be a stage before cognitive decline progresses to dementia. If the default mode network has the potential to be a biomarker, then it could be developed into an objective test of early cognitive decline.

Holmes analyzed MRI scans from 22 healthy older adults and observed that the front region of the default mode network might be correlated with subjective cognitive decline.

“I really want to do research, and I also want to be a practitioner as well, working with either hospitals or university hospitals to help patients,” he said.

Investing in research trainees like Holmes is one way that NIA inspires the next generation of scientists to focus on Alzheimer’s and related dementias. In the fall of 2021, Holmes will begin his graduate program at the University of Florida, pursuing a Ph.D. in clinical neuropsychology.