Accelerating Development of Tools To Support Dementia Diagnosis and Cognitive Assessment

In addition to the amyloid plaques and tau tangles that characterize Alzheimer’s, there are other factors that contribute to Alzheimer’s and related dementias, including cerebrovascular disease, aggregations of other proteins, and more. It is often the case that multiple pathologies are present in an individual with dementia. Sensitive, affordable diagnostic techniques and cognitive assessments — validated among diverse populations — help clinicians diagnose the correct condition(s) and understand disease stages, and are therefore crucial to preventing and treating dementia.

Cognitive assessments

Face-to-face cognitive assessment, in which an individual is assessed by a clinician using a battery of relevant tests, remains the gold standard for detection of cognitive impairment. However, it is important that health care providers can perform a cognitive assessment within an average medical visit, which may only last 15 minutes or less. NIH-funded researchers are developing accurate and highly sensitive tests that can detect potential issues quickly, and in some cases, outside the clinic. For example, an NIH-funded study demonstrated the feasibility and reliability of measuring individuals’ learning curves while repeating the same brief battery of memory tests over seven days. The participants — cognitively normal older adults — completed the tests at home on their own laptops and smartphones. Researchers found that information collected at home was comparable to traditional cognitive measures. Next, the investigators plan to assess the ability of this at-home test to detect mild cognitive impairment or early-stage dementia.

NIH-funded researchers have also developed a web-based cognitive test (PDF, 395K), available in English and Spanish, that can detect mild cognitive impairment. The test takes under 15 minutes to complete and can be performed without the need for a skilled test administrator. Researchers found that the test was able to distinguish between people with normal cognition and those with mild cognitive impairment. They also found that test scores were associated with the size of brain regions affected in Alzheimer’s among persons with mild cognitive impairment, supporting its usefulness as a potential screening test for cognitive decline.

Fluid biomarkers

Although advances in brain imaging are generating exciting findings, the imaging modalities used in dementia research are often only available at specialized medical centers and can be expensive and often impractical for individuals with cognitive impairment. However, simple blood tests are emerging that can support a diagnosis or risk evaluation in the doctor’s office. With support from NIH small business funding, C2N Diagnostics released a second-generation blood test in 2023 that combines measures of amyloid and tau to help physicians make an accurate and timely diagnosis. This test, PrecivityAD2, and the earlier PrecivityAD test, can help lower costs and increase access to diagnostic tools for Alzheimer’s.

Other dementia-related tests using blood and plasma may not be far behind. Researchers have found that levels of another form of tau, p-tau181 , in blood are associated with cognitive performance and reliably differentiate cognitively impaired and nonimpaired individuals. In addition, higher levels of p-tau181 are associated with more rapid cognitive and functional decline. Baseline plasma levels of p-tau181 and glial fibrillary acidic protein (GFAP), a protein expressed by support cells in the central nervous system, can predict cognitive decline over the following four years, and GFAP levels correlate with severity of clinical symptoms in Alzheimer’s.

The cerebrospinal fluid (CSF), which bathes the brain and spinal cord, also contains biomarkers that can predict or diagnose neurodegenerative diseases. For example, NIH-funded researchers recently validated the first tau biomarkers in CSF . Just a few years ago, changes in tau levels could only be reliably measured via PET scan, a complex and expensive process. The identification of biomarkers for tau in the CSF will make it easier for researchers and clinicians to diagnose Alzheimer’s and other dementias and monitor treatment response.

In a separate study, NIH-funded researchers found that changes in levels of a protein called neuronal pentraxin 2 (NPTX2) , which supports communication among brain cells, have been shown to predict development of mild cognitive impairment among cognitively normal middle-aged adults. In another study, NIH-funded investigators measured proteins in CSF and identified biomarker profiles highly specific for Lewy body dementia , a disease for which diagnosis is challenging. The investigators have used this information to translate these findings to a biomarker panel that may help accurately identify Lewy body dementia, potentially paving the way for improved diagnostics and clinical trials.

Digital tools

Researchers are increasingly using emerging “big data” methods to identify individuals at risk of dementia and even detecting undiagnosed dementia in real-world populations. For example, the eRADAR tool , which analyzes routinely collected data from electronic health records to detect undiagnosed dementia, was recently validated in separate populations and across racial and ethnic groups. Once individuals with potential undiagnosed dementia are identified, they can be referred for further assessment and, potentially, enrollment in a clinical trial.

Emerging and future biomarkers

Researchers continue to identify and develop next-generation biomarkers that may be less invasive and less expensive than those currently available to researchers and clinicians. The expanding field of brain imaging biomarkers — that is, changes in the architecture of the brain as well as the shapes of proteins visualized using state-of-the-art techniques — has opened doors to new and more accurate diagnoses. It has also enabled researchers to learn more about the brain and about potential risk factors or markers for cognitive decline. For example, researchers found that cognitively healthy people with less myelin , the fatty tissue that protects nerve cells, experience more rapid cognitive decline over time. Further research is needed to clarify the relationship between myelin integrity and cognition.

Researchers are also working to facilitate biomarkers beyond brain imaging. For example, beta-amyloid, a protein found in the brains of individuals with Alzheimer’s, can also be detected easily and noninvasively in the retina. Recent studies of postmortem tissue showed that levels of amyloid in the retina were higher in people with Alzheimer’s than in people with mild cognitive impairment, suggesting that a simple eye test could be used both to detect and track progression of Alzheimer’s. In another study, NIH-funded investigators found that a PET scan of the heart may help identify people who will go on to develop Parkinson’s disease or Lewy body dementia among at-risk individuals by revealing low levels of norepinephrine, a hormone that is depleted in these diseases.

Biomarkers in plasma, the liquid component of blood, are also being explored for utility in distinguishing Alzheimer’s from LATE-NC, which is clinically similar to Alzheimer’s and often overlaps with both Alzheimer’s and Lewy body pathology. For example, research has shown that plasma levels of the protein TDP-43 , which is implicated in LATE-NC, are associated with the condition’s characteristic structural changes in the brain. Blood-based measurement of TDP-43 accumulation in tiny particles known as extracellular vesicles, particularly those derived from specific types of brain cells, also shows promise as a diagnostic tool for LATE-NC.

TDP-43 is also being explored as a biomarker for other forms of neurodegenerative diseases. For example, using donated brain tissue, researchers identified a unique form of amyloid filament formed by TDP-43 in a specific type of frontotemporal dementia. These findings could help guide the development of diagnostic and therapeutic compounds for disorders associated with TDP-43 accumulation.

Furthermore, research has revealed that TDP43 dysfunction is common in Alzheimer’s and is associated with greater disease severity. NIH-funded investigators are currently exploring the role of cryptic RNAs — snippets of genetic material that can interfere with a cell’s function — in Alzheimer’s. Researchers have found that the same cryptic RNAs that indicate TDP-43 dysfunction in ALS and frontotemporal lobar degeneration are present in Alzheimer’s with TDP43 dysfunction, suggesting potential diagnostic and therapeutic targets and hinting at a common mechanism among these disorders.

Spotlight: NIH PREPARE (EUREKA) Challenge

Existing cognitive tests are not always sensitive enough to identify subtle signs of cognitive decline at the earliest stages of the disease course when treatment may be most effective. Moreover, the predictive power of current tests can vary among population groups, which may result in less effective screening and diagnosis of dementia in groups that have been historically underrepresented in research.

To address this need and spur the development of solutions to improve early prediction of dementia symptoms among diverse populations, NIH launched the Pioneering Research for Early Prediction of Alzheimer’s Disease & Related Dementias EUREKA (PREPARE) Challenge in fall 2023. This challenge, which consists of three phases, is intended to stimulate creativity and innovation through the award of substantial cash prizes.

Phase 1 of the challenge, which ran from September 2023 to January 2024, emphasized identifying datasets to support early prediction of dementia, especially in historically underrepresented groups. Phases 2 and 3, slated to begin in September 2024 and March 2025, respectively, will foster approaches to develop and use ethical and inclusive algorithms to support early prediction of dementia. Challenge winners are expected to share widely their findings, learnings, and approaches to enable impactful real-world translation.

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