Early brain connectivity decline tied to Alzheimer’s disease progression

In a recent study published in the journal Alzheimer’s & Dementia, researchers have discovered that the connectivity between the locus coeruleus and the medial temporal lobe can be an early indicator of Alzheimer’s disease-related brain atrophy and cognitive decline. They found that lower connectivity between these brain regions during a novelty task was associated with faster atrophy in regions typically affected by Alzheimer’s disease.

The motivation behind the new study stemmed from the need to understand the early mechanisms of Alzheimer’s disease, which is 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 brainstem nucleus involved in norepinephrine production, 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 brain regions, and that the locus coeruleus plays a critical role in cognitive functions such as memory and attention. The researchers hypothesized that changes in the connectivity between the locus coeruleus and the medial temporal lobe might be linked to brain atrophy and cognitive decline in Alzheimer’s disease.

“The locus coeruleus, a small nucleus in the brainstem, provides norepinephrine to the entire brain,” explained study author Heidi Jacobs, an associate professor of radiology at Massachusetts General Hospital and Harvard Medical School.

“Norepinephrine is a neurotransmitter that supports many cognitive functions and behaviors, for example memory, stress, sleep. Furthermore, the locus coeruleus is one of the first regions in the brain to accumulate Alzheimer’s disease related pathology. Examining changes in the locus coeruleus can 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 cognitively unimpaired older adults 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, as previous animal studies have shown that the locus coeruleus responds strongly to novel stimuli.

In addition to the functional MRI, participants underwent amyloid beta PET scans to measure the levels of amyloid plaques in the brain. Structural MRI scans were conducted regularly to assess brain atrophy over time. Cognitive performance was evaluated using a composite score from multiple cognitive tests, designed to detect early signs of Alzheimer’s disease-related decline.

The researchers found that lower connectivity between the locus coeruleus and the medial temporal lobe during the novelty task was associated with faster atrophy (shrinkage) in the medial temporal lobe, particularly in regions affected early in 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.

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Importantly, they discovered that atrophy in the medial temporal lobe mediated the relationship between locus coeruleus-medial temporal lobe connectivity and cognitive decline. In simpler terms, lower connectivity led to faster brain shrinkage, which in turn led 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 faster atrophy, and together these two events led to cognitive decline in individuals in the earliest stages of Alzheimer’s disease,” Jacobs told PsyPost.

The findings from this study suggest that enhancing the connectivity between the locus coeruleus and the medial temporal lobe could be a potential strategy for slowing down Alzheimer’s disease progression. Some animal studies have shown that stimulating the locus coeruleus can improve memory and protect against neurodegeneration, which aligns with the human data observed in this study.

While the study provides compelling evidence for the role of locus coeruleus-medial temporal lobe connectivity in Alzheimer’s disease progression, there are some limitations. Firstly, the locus coeruleus is a very small brain structure, making it challenging to measure accurately using current imaging techniques. The researchers took several steps to mitigate these challenges, but some degree of error is unavoidable.

Additionally, the study population was predominantly White and highly educated, which may limit the generalizability of the findings. Future research should aim to replicate these results 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 can modify the course of Alzheimer’s disease at its earliest stages.

“In the future, we would like to investigate if stimulating the communication between the locus coeruleus and these memory brain regions with non-invasive brain stimulation methods can delay cognitive decline,” Jacobs said.

The study, “Atrophy links lower 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 I. L. Jacobs.