In a recent study published in the journal Alzheimer’s and dementia, researchers have discovered that connectivity between the locus coeruleus and the medial temporal lobe may be an early indicator of brain atrophy and cognitive decline linked to Alzheimer’s disease. They found that weaker connectivity between these brain regions during a novel task was associated with faster atrophy in regions typically affected by Alzheimer’s disease.
The motivation behind this new study stems from the need to understand the early mechanisms of Alzheimer’s disease, characterized by the accumulation of amyloid beta and tau proteins, leading to neurodegeneration and cognitive decline. The researchers aimed to explore the role of the locus coeruleus, a small nucleus in the brainstem involved in the production of norepinephrine, in the early stages of Alzheimer’s disease.
Previous studies have shown that tau protein accumulation begins in the locus coeruleus before spreading to other regions of the brain, and that the locus coeruleus plays a critical role in cognitive functions such as memory and attention . Researchers hypothesized that changes in connectivity between the locus coeruleus and the medial temporal lobe may be linked to brain atrophy and cognitive decline in Alzheimer’s disease.
“The locus coeruleus, a small nucleus in the brainstem, supplies norepinephrine to the entire brain,” explained study author Heidi Jacobs, associate professor of radiology at Massachusetts General Hospital and Harvard Medical. School.
“Norepinephrine is a neurotransmitter that supports many cognitive functions and behaviors, e.g. memory, stress, sleep. In addition, the locus coeruleus is one of the first regions of the brain to accumulate pathologies linked to Alzheimer’s disease. Examining changes in the locus coeruleus may help us identify Alzheimer’s disease earlier, understand the mechanisms underlying disease progression, and will also allow us to develop interventions to delay the disease.
For their study, the researchers analyzed data from 128 older adults without cognitive impairment who were part of the Harvard Aging Brain Study, a longitudinal research project focused on aging and preclinical Alzheimer’s disease. Participants performed a face-name association task while undergoing functional MRI. This task involved memorizing pairs of faces and names, with some pairs being novel and others repeated. The novelty blocks were designed to evoke phasic activity in the locus coeruleus, because previous animal studies have shown that the locus coeruleus responds strongly to novel stimuli.
In addition to functional MRI, participants underwent beta-amyloid PET to measure levels of amyloid plaques in the brain. Structural MRI scans were performed regularly to assess brain atrophy over time. Cognitive performance was assessed using a composite score from several cognitive tests, designed to detect early signs of Alzheimer’s disease-related decline.
The researchers found that weaker connectivity between the locus coeruleus and the medial temporal lobe during the novelty task was associated with faster atrophy (shrinkage) of the medial temporal lobe, particularly in regions affected early in life. Alzheimer’s disease (known as Braak stage 2 regions). This relationship was stronger in individuals with higher levels of amyloid beta, suggesting that the presence of this protein exacerbates the effects of reduced connectivity.
Importantly, they found that medial temporal lobe atrophy mediated the relationship between locus coeruleus-medial temporal lobe connectivity and cognitive decline. In simpler terms, less connectivity caused the brain to shrink more quickly, leading to worse cognitive performance over time. This mediation effect was more pronounced in individuals with higher amyloid-beta levels, highlighting the interaction between these two pathological markers of Alzheimer’s disease.
“We showed that reduced communication between the locus coeruleus and key memory regions in the brain was associated with more rapid atrophy, and together these two events led to cognitive decline in individuals in the early stages of Alzheimer’s disease,” Jacobs told PsyPost.
The results of this study suggest that improving connectivity between the locus coeruleus and the medial temporal lobe may be a potential strategy to slow the progression of Alzheimer’s disease. Some animal studies have shown that stimulation of the locus coeruleus can improve memory and protect against neurodegeneration, which is consistent with the human data observed in this study.
Although the study provides compelling evidence for the role of locus coeruleus-medial temporal lobe connectivity in the progression of Alzheimer’s disease, it has some limitations. First, the locus coeruleus is a very small brain structure, making it difficult to measure accurately using current imaging techniques. Researchers have taken several steps to mitigate these challenges, but some degree of error is inevitable.
Additionally, the study population was predominantly white and highly educated, which may limit the generalizability of the results. Future research should aim to replicate these findings in more diverse populations to ensure broader applicability.
Future studies could also aim to investigate the exact mechanisms by which amyloid beta and tau proteins influence locus coeruleus connectivity and subsequent brain atrophy. Understanding these pathways could lead to the development of targeted interventions that could modify the course of Alzheimer’s disease from its earliest stages.
“In the future, we would like to study whether stimulating communication between the locus coeruleus and these memory regions of the brain with non-invasive brain stimulation methods can delay cognitive decline,” Jacobs said.
The study, “Atrophy Links Novelty-Related Locus Coeruleus Connectivity to Cognitive Decline in Preclinical AD,” was authored by Christoph Schneider, Prokopis C. Prokopiou, Kathryn V. Papp, Nina Engels-Domínguez, Stephanie Hsieh, Truley A. Juneau, Aaron P. Schultz, Dorene M. Rentz, Reisa A. Sperling, Keith A. Johnson, and Heidi IL Jacobs.