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Research Highlights

Inside the brain: The role of neuropathology in Alzheimer’s disease research

Imagine being able to look inside the brain of a person with Alzheimer’s disease and see the changes that are interfering with that person’s thinking, memory, and other important brain functions. Scientists working in the field of neuropathology are doing just that.

Using a variety of methods, neuropathologists view patterns of abnormal protein clusters and cellular damage in brain tissue under a microscope and through computer-driven imaging. They use that information to characterize the changes that occur in the brain with particular diseases or conditions.

For example, in 1906, the psychiatrist and neuropathologist Alois Alzheimer first identified the abnormal buildup of protein fragments — amyloid plaques and neurofibrillary (tau) tangles — in the brain tissue of a woman who had died from a previously unknown disease that caused a decline in her ability to think, remember, and speak. This illness was later named Alzheimer’s disease, which is the most common form of dementia. Neuropathologists today continue to actively work on identifying the changes that can be seen in the brain after death and connecting those to symptoms and biological processes observed during life.

Long before the symptoms of memory loss appear, many molecular and cellular changes take place in the brain of a person with Alzheimer’s. Neuropathology research has been essential in helping to identify these biological changes, called biomarkers, and revolutionizing the methods scientists and doctors can use to diagnose and treat these diseases. For example, 20 years ago, the only sure way to know whether a person had Alzheimer’s was through autopsy. Since then, researchers have developed and tested methods to “see” evidence of protein fragments associated with Alzheimer’s on brain scans, in cerebrospinal fluid, and even in blood while people are still alive. Being able to diagnose Alzheimer’s in the early stages is helping researchers to test new treatments that may slow or stop progression of the disease.

Still, as far as neuropathology has evolved, there is much to learn. For example, not everyone with amyloid plaques and tau tangles — the hallmark signs of Alzheimer’s — will eventually develop this disease. In addition, many people who are diagnosed with Alzheimer’s dementia have evidence of other pathologies in their brain, either instead of or in addition to those associated with Alzheimer’s. What factors influence the development of these different dementia-related pathologies? How can science help to better identify the underlying causes of dementia symptoms, so that we can better diagnose, treat, and prevent dementia? What causes the variability in the rate, severity, and type of cognitive decline among people with Alzheimer’s?

To address these questions and other complexities of dementia diseases, NIA-supported researchers are using the power of neuropathology in both traditional and innovative ways. For example, large studies of healthy adults over many years, new technologies to understand changes in individual brain cells, and collaboration among scientists with different expertise is equipping researchers with the information needed to map the connections between brain changes and risk factors that lead to dementia.

Neuropathology led to the discovery of Alzheimer’s disease and continues to provide invaluable insights today. NIA supports a wide range of neuropathological research to identify how and why these brain changes happen and to help develop tailored treatment and prevention strategies across diverse populations.

— Nina Silverberg, Ph.D., director of the NIA Alzheimer's Disease Research Centers program

ROSMAP: Community studies fuel research on aging and Alzheimer’s

To understand more about the causes of Alzheimer’s and related dementias, NIA-funded researchers across the country are making connections between what happens while a person is alive and what can be seen in their brain after death. This approach provides insights about factors that increase the risk of developing dementia as well as what may provide some protection against these diseases.

One such effort is the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), referred to collectively as ROSMAP. ROS launched in 1994 and enrolls Catholic nuns, priests, and brothers from across the United States. MAP began in 1997 to study older adults who live in northeastern Illinois and the Chicago metropolitan area. Older adults are recruited primarily from continuous care retirement communities, retirement homes, and senior subsidized housing facilities, as well as through local churches and other social service agencies serving underrepresented communities.

All ROSMAP participants enroll without symptoms of dementia. They agree to annual evaluations and to donate their brain after death, and in some cases, to donate their spinal cord, nerves, and muscles. The researchers meet with the volunteers annually to collect brain scans and blood tests, track any changes in cognition and motor function, and gather information about each participant’s lifestyle and behaviors.

The combination of lifestyle and autopsy information collected over the past 25 years makes ROSMAP a powerful resource for researchers around the world to study aging and dementia risk and progression. The Rush Alzheimer’s Disease Research Center, led by Julie A. Schneider, M.D., M.S., professor of pathology at Rush Medical College in Chicago, has completed more than 1,700 autopsies, which represents more than 80% of the ROSMAP participants who have died. Of those autopsied, roughly 40% had Alzheimer’s dementia.

However, further examination of the donated brain tissue after death reveals that multiple pathologies are at play. In other words, while Alzheimer’s pathology — amyloid plaques and tau tangles — is present in most cases of clinically diagnosed Alzheimer’s dementia, other accumulations of different types of protein fragments or misfolded proteins are also often present, along with damage to blood vessels, or vascular pathology.

All of these other pathologies have a cumulative effect in the brains of people who have what we call Alzheimer’s dementia.

— Julie A. Schneider, M.D., M.S., professor of pathology at Rush Medical College in Chicago

Moreover, the number and combinations of neuropathologies vary greatly among individuals and the effects of these combinations on thinking and memory differ as well. This variability among individuals reflects the complexity of Alzheimer’s disease and the need to understand how these pathologies interact and who is at risk. One ROSMAP study identified several genes that may have roles in the brain changes that occur in Alzheimer’s. Currently, Schneider and her colleagues are studying the effects of other risk factors — including sleep and sleep disruption, and traumatic brain injury — on the development of pathologies associated with dementia.

By studying healthy older adults over many years, ROSMAP researchers are also discovering important clues about factors that may offer some protection from cognitive decline and dementia. According to ROSMAP autopsy data, nearly one third of older adults who die with no signs of cognitive decline have the amyloid plaques and tau tangles associated with Alzheimer’s disease. How is it possible that these people have the hallmark signs of Alzheimer’s but no symptoms? Researchers are exploring many avenues to answer this question. One such ROSMAP study found that eating the MIND diet — which focuses on plant-based foods and limits red meat, sweets, and saturated fats — helps to preserve cognition even in the presence of some Alzheimer’s pathology. Building on these results, ROSMAP researchers and others are continuing to study diet and other lifestyle factors that may help lower the risk or slow cognitive decline in Alzheimer’s and related dementias brain pathologies.

90+ Study: Learning from the oldest-old

Researchers can learn a lot about how Alzheimer’s develops by studying people at increased risk. People older than age 90, or the oldest-old, are the fastest growing segment of the population in the United States and most of the world and have the highest rates of dementia. Remarkably, the oldest-old also have the highest rate of cognitive resilience and somehow avoid developing dementia despite having brain pathologies. This populations’ high rates of dementia, yet also resilience, make it an optimal group to study to understand the underlying causes of dementia.

The 90+ Study, launched in 2003, is one of the largest and longest studies researching dementia, cognitive decline, and other aspects of aging in the oldest-old. Funded by NIA and led by Claudia Kawas, M.D., professor of neurology and behavior at the University of California, Irvine (UCI), and clinical core co-leader at the UCI Alzheimer’s Disease Research Center, the 90+ Study enrolls people over 90 years old with and without cognitive decline. The study team reviews medical records, tracks changes in cognition and function, collects brain images, and assesses social factors such as lifestyle and education. Many of the study participants also donate their brains when they die for autopsy analysis.

Similar to the ROSMAP findings, Kawas and her team have found that at least half of all dementia in this age group is due to pathologies other than Alzheimer’s, such as vascular disease or abnormal accumulations of protein fragments other than amyloid plaques and tau tangles. Additionally, they have linked the presence of multiple pathologies to an increased risk of dementia, rate of decline, and severity of the dementia.

This complexity makes diagnosing the cause of cognitive problems and dementia in the oldest-old particularly challenging. But knowing that this complexity exists helps to account for all the variability we see, such as in the rates of cognitive decline, according to Kawas. Through ongoing studies, she and others are now examining why these different pathologies occur and how the different pathologies interact and contribute to dementia.

At the same time, there is still much to learn from the oldest-old about the factors that protect people from Alzheimer’s dementia. Remarkably, the 90+ study reports that approximately 40% of adults over age 90 have mild to moderate amounts of Alzheimer’s or other dementia-related pathology, but don’t have dementia symptoms.

“That’s really what we all want,” Kawas said. “Most of us don’t care what’s in our brains if we’re still able to do whatever we want to do.”

By studying these exceptional people, Kawas and other scientists hope to uncover ways to help prevent dementia in people of all ages.

Learn more about cognitive resilience and cognitive super agers.

Discovery of new dementias with symptoms like Alzheimer’s

Sometimes what looks like Alzheimer’s disease is not, as findings from both the ROSMAP and 90+ studies show. Peter T. Nelson, M.D., Ph.D., professor of pathology and laboratory medicine at the University of Kentucky (UK), and neuropathology core leader at the UK Sanders Brown Center and Alzheimer’s Research Disease Center, is conducting NIA-funded research to identify and understand how these other brain pathologies contribute to dementia.

Over multiple years, neuropathologists noticed, during autopsy, that the brains of many older adults had tau tangles like those seen in Alzheimer’s. However, unlike Alzheimer’s disease, these brains lacked amyloid plaques. In 2014, Nelson, in collaboration with NIA and a team of top Alzheimer’s researchers, named this pathology PART, or primary age-related tauopathy.

Continuing research indicates that PART is a relatively common pathology that develops as people age. Alone, PART leads to mild cognitive decline that occurs at a slower rate than Alzheimer’s disease. However, when combined with other pathologies, such as Lewy bodies, PART can increase the severity of memory and thinking problems. While the tau tangles of PART pathology are like what is seen in Alzheimer’s, PART pathology is found in different parts of the brain. Researchers are actively studying these differences to both understand how PART affects cognition and to identify biomarkers that could distinguish PART from early Alzheimer’s.

Another brain disease associated with symptoms like Alzheimer’s disease is called LATE, or limbic-predominant age-related TDP-43 encephalopathy. In LATE, abnormal clusters of the protein TDP-43 form between neurons, and these deposits are associated with the deterioration of parts of the brain involved in memory, such as the hippocampus. The result is substantial cognitive impairment that symptomatically looks like Alzheimer’s dementia. Like PART, when LATE is combined with other pathologies, such as Alzheimer’s, cognitive decline is faster and more severe.

Results from large autopsy studies suggest that more than 20% of people over 80 years old are affected by LATE, and it frequently occurs along with Alzheimer’s pathology. Currently, there is no way to diagnose LATE in people while living. Researchers are working to identify specific biomarkers for LATE that could be developed into diagnostic tools to be used by doctors. For example, researchers are currently examining ROSMAP data to explore whether LATE has a unique pattern of brain degeneration and memory loss that could help distinguish it from Alzheimer’s disease. Other efforts are aimed at finding a unique molecular signature for LATE that might be used to create a blood or spinal fluid diagnostic test.

LATE-specific biomarkers would also enable researchers to track the progression of LATE pathology to understand how the disease progresses over time. Since the cognitive symptoms of LATE and Alzheimer’s look the same, LATE biomarkers are also needed to improve screening people for clinical trials.

We need better ways of figuring out who has what during life. These discoveries are an important shift for Alzheimer’s research. By knowing that these different pathologies exist, the field is getting closer to unraveling the complexity of Alzheimer’s.

— Peter T. Nelson, M.D., Ph.D., professor of pathology and laboratory medicine at the University of Kentucky

Nelson compares the recognition of Alzheimer’s complexity to the cancer research path.

“In the 1990s, researchers started discovering that there were a lot of interesting biological pathways that lead to different cancers. Researchers wrestling with that complexity has led to targeted treatments. We’re at that same point with Alzheimer’s research.”

To this end, NIA’s network of Alzheimer’s Disease Research Centers, along with other NIA-funded scientists, are following participants from different communities for many years to provide, as Nelson describes it, “an evolving picture of what is actually present in the aging brains of people around the world.”

A novel platform to support precision neuropathology research

To capture an integrated picture of what is happening in both the tissue and at cellular level of the brain, C. Dirk Keene, Ph.D., the Nancy and Buster Alvord endowed chair in neuropathology at the University of Washington (UW), and the neuropathology core leader for the UW Alzheimer’s Disease Research Center, and his colleagues are combining traditional pathology methods with new state-of-the-art technologies to understand changes in individual brain cells. 

This approach, called precision neuropathology, allows Keene and his team to analyze individual brain cells collected from autopsies, and determine which proteins are present, what genes are turned on or off, and the activity of different cellular processes and pathways.

Importantly, this approach can be used to analyze different types of cells in the brain, including immune cells and neurons that were dead or were in the process of dying. By studying various cells in different stages of the disease process, Keene and his colleagues can gain insights into the effects of the disease inside and between cells in the brain.

“Ultimately, this approach, combined with clinical information, will lead to a multidimensional understanding of Alzheimer’s disease progression and complexity,” Keene said.

The goal is to identify new proteins and pathways that can be targeted for the right treatment at the right time, possibly even before clinical symptoms appear. Keene notes that none of this research could be conducted without the generous gifts of brain donation.

Brain donation is one of the greatest gifts that a patient and family can give to science. It’s what has helped us get to the point where we are today with Alzheimer’s disease research.

— C. Dirk Keene, M.D., Ph.D., Nancy and Buster Alvord Endowed Chair in Neuropathology, University of Washington

Keene believes that sharing resources is the key to maximizing the knowledge gained from each donated brain. He and others are committed to sharing brain tissue and creating online databases to make autopsy and research data collected on each brain freely available and accessible to researchers around the world. For example, Keene has been leading a collaborative effort among the NIH NeuroBioBank, the Brain Donor Project, and the Alzheimer’s Disease Research Centers’ brain banks, which provide the scientific community with access to brain tissue and associated neuropathology information along with any linked clinical or research data. He is hopeful and excited about the many new scientists from a range of other fields who are transitioning to Alzheimer’s and dementia research, bringing new expertise and ideas.

Looking ahead

Understanding how Alzheimer’s and related disease pathologies develop and interact to cause dementia is an evolving story. The remarkable discoveries of new pathologies that trigger symptoms like Alzheimer’s disease inspires many new research questions such as what causes them? How can they be detected? And most important, how can they be detected and treated before symptoms appear? In addition, as researchers learn more about the variety of underlying pathologies — and that a person’s dementia symptoms may have multiple causes — it is clear that a variety of treatments may be needed. It is also quite possible that there are other dementia-related pathologies that have yet to be discovered. Neuropathology research holds the keys to these and related discoveries.

Moreover, increasing diversity in neuropathology research is essential to understanding how Alzheimer’s and related dementias occurs in all people and how we can develop effective treatment and prevention strategies. Several efforts by NIA-funded researchers are underway to engage people of different races and ethnicities, genders, and sexual orientations, and with varied exposure to environmental risk factors, to consider participating in research on Alzheimer’s and related dementias.

“NIA’s investment in neuropathology research and the increasing inclusion of diverse participants in this research is leading to exciting discoveries and bringing us closer to a world in which we can diagnose and treat dementia early,” said Silverberg.