Skip to content

Functional MRI of Locus Coeruleus Might Detect Risk of Alzheimer's Disease

Key findings

  • The hallmarks of Alzheimer's disease are the deposition of beta-amyloid (Aβ) plaques and misfolded tau proteins in the brain. The locus coeruleus (LC) is one of the first regions of the brain to be affected by misfolded tau proteins
  • This study investigated whether the neuronal activity and functional connectivity of the LC are associated with cognitive decline in conjunction with Aβ
  • For 128 healthy, cognitively intact older individuals, longitudinal cognitive data were reviewed along with baseline imaging data: positron emission tomography of Aβ and functional MRI obtained during a novel vs. repeated face–name association test
  • Lower novelty-related LC activity and functional connectivity between the LC and hippocampus, and parahippocampus, were associated with a steeper decline in cognition measured over 10 years, particularly in the presence of elevated Aβ deposition
  • These results demonstrate the potential of LC function to serve as a gauge of whether individuals are at risk of Alzheimer's disease-related cognitive decline

In people who develop Alzheimer's disease, the locus coeruleus (LC) is one of the first sites in the brain to be affected by beta-amyloid (Aβ) plaques and misfolded tau proteins. The LC is a subcortical nucleus that provides norepinephrine to the entire brain.

Previous research has shown the LC is highly responsive to novelty, leading to norepinephrine release in the amygdala and hippocampus that contributes to learning. Researchers at Massachusetts General Hospital have now determined that novelty-related neuronal activity and functional connectivity of the LC may be early indicators of the risk of cognitive decline. Prokopis C. Prokopiou, PhD, a research fellow at the Gordon Center for Medical Imaging at Mass General, Nina-Engels Domínguez, clinical research project manager and PhD student, and Heidi I.L. Jacobs, PhD, an assistant professor of Radiology associated with the Gordon Center, and colleagues report the findings in Nature Communications.


The researchers reviewed data on 128 participants (71 women) in the Harvard Aging Brain Study, an ongoing longitudinal observational study. At baseline, the age range was 50 to 89 (median, 70). All participants were cognitively unimpaired and were also free of medical and psychiatric diseases.

Based on positron emission tomography at baseline, 92 participants were classified as having low Aβ, and 36 had elevated Aβ. At baseline, all participants also underwent functional MRI while they performed an associative memory test. They tried to learn face-name pairs as unfamiliar faces were shown either a single time (novelty) or multiple times (repetition).

Participants completed neuropsychological evaluations for up to 10 years (median follow-up, 4.25 years).

Novelty vs. Repetition

LC activity and LC functional connectivity with the amygdala and hippocampus were higher during novelty compared with repetition. This rearrangement for processing novel stimuli is presumably important for reallocating sufficient cognitive resources to tasks such as attentional shifts and learning.

LC Activity and Cognitive Decline

Lower novelty-related bilateral LC activity and lower LC functional connectivity with the hippocampus and parahippocampus were associated with worse performance on neuropsychological tests and steeper Aβ-related cognitive decline. This was especially true in patients who had elevated Aβ at baseline.

Toward Clinical Translation

Lower novelty-related LC function might be able to identify clinically healthy individuals who are at risk of cognitive decline that can progress to Alzheimer's disease. In contrast, individuals able to maintain optimal levels of novelty-related LC function may be more resilient to cognitive decline, even in the presence of elevated Aβ.

Learn about the Gordon Center for Medical Imaging

Refer a patient to the Department of Radiology


Binyin Li, MD, David H. Salat, PhD, and colleagues created a machine learning classifier that detected Alzheimer's disease–like brain patterns in younger adults (40 to 59 years old) and in a cohort with mild cognitive impairment.


Massachusetts General Hospital researchers found an MRI measure of locus coeruleus (LC) integrity starts declining about 12 years before symptom onset in autosomal dominant Alzheimer's disease. This and related findings suggest LC integrity is a promising prognostic indicator in the preclinical stage of the disease.