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Changes in a small area in the brainstem could help detect Alzheimer’s disease earlier

An area of the brain called the locus coeruleus, sometimes called “the blue spot,” might show signs of Alzheimer’s disease before any other brain area does, according to a recent NIA-supported study. Published in Science Translational Medicine, the findings suggest a potentially promising new early indicator for Alzheimer’s disease.Computer graphic of magnified tau protein, shaded in pink and orange, inside a neuron.

In Alzheimer’s disease, tau protein accumulates in cells throughout the brain and forms tangles. Tau tangles, along with the accumulation of amyloid, another type of protein that forms plaques, are two hallmarks of Alzheimer’s disease. Treating Alzheimer’s disease is a challenge, in part because it is usually diagnosed after the onset of symptoms when significant damage in the brain has already occurred. However, by using new advancements in brain imaging, scientists from Massachusetts General Hospital may be one step closer to diagnosing Alzheimer’s, even before cognitive deficits emerge.

The locus coeruleus is a small area of the brain located in the brainstem. It gets its nickname “the blue spot” because the cells in the area produce a blue pigment that makes the whole region appear blue. Many researchers who study Alzheimer’s are interested in the locus coeruleus because it seems to accumulate tau long before any noticeable clinical signs of the disease arise. However, the size of the area, and the type of brain cells within it, make the locus coeruleus difficult to image with normal magnetic resonance imaging (MRI) and positron emission tomography (PET) scans.

In this study, the team of scientists used a new technique to look at the signal intensity of the locus coeruleus. This signal intensity gives information about the number and health of cells in the region. A lower signal indicates that neurons may be damaged, which can be a sign of tau accumulation.

To conduct the study, scientists utilized data from 174 participants from the Harvard Aging Brain Study, some of whom had cognitive impairment, while others had normal brain function. All participants underwent MRI and PET brain imaging and most received repeated long-term assessments to measure brain functions, such as memory and attention, as part of the larger aging brain study.

Using the high-resolution MRI together with PET scans that identify tau tangles and plaques in other brain areas, the scientists made an important connection. They found that a low-intensity signal from the locus coeruleus was associated with an increased presence of tau tangles and amyloid plaques in an area of the brain called the entorhinal cortex, which is involved in memory function. The scientists also found that a weaker signal from the locus coeruleus was associated with a loss of memory and a decline of other brain functions.

To confirm their results, the scientists compared the imaging findings against autopsy data from two established datasets, the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and the National Alzheimer’s Coordinating Center (NACC). These datasets contain postmortem assessments of locus coeruleus damage, brain function, and Alzheimer’s-induced cellular damage in numerous other areas. Similar to the results from the high-resolution MRI, the researchers found that participants whose autopsy results showed tau tangles in the locus coeruleus also showed Alzheimer's-related brain damage and a decline in brain function.

Scientists do not know how, or if, tau moves from the locus coeruleus to other brain areas. However, findings from this study show that changes in the locus coeruleus could be a promising marker to indicate the brain’s tau tangle and amyloid plaque burden and have the potential to help providers evaluate an individual’s risk for cognitive decline. This research paves the way for advances in the early detection of Alzheimer’s, which may increase the chances of successful treatment.

This research was funded in part by NIA grants P01AG036694, R01AG046396, R01AG062559, 30AG10161, R01AG1581, R01AG17917, R01AG050436, R01AG052414, U01AG016976, U01AG032984, P30AG019610, P30AG013846, P30AG062428-01, P50AG008702, P50AG025688, P50AG047266, P30AG010133, P50AG005146, P30AG062421-01, P30AG062422-01, P50AG005138, P30AG008051, P30AG013854, P30AG008017, P30AG010161, P50AG047366, P30AG010129, P50AG016573, P30AG062429-01, P50AG023501, P30AG035982, P30AG028383, P30AG053760, P30AG010124, P50AG005133, P50AG005142, P30AG012300, P30AG049638, P50AG005136, P30AG062715-01, P50AG005681, and P50AG047270.

These activities relate to NIH’s AD+ADRD Research Implementation Milestone 9.A, “Develop and validate translatable biomarkers for their use in preclinical and clinical drug development. These efforts should include the development of pharmacodynamic biomarkers of target engagement, biomarkers of incipient disease (ocular, olfactory) and biomarkers for detection and tracking of synaptic dysfunction.”

Reference: Jacobs HIL, et al. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline. Science Translational Medicine. 2021;13(612):eabj2511. doi: 10.1126/scitranslmed.abj2511