Research Spotlight: Early Targeting of the Locus Coeruleus May Delay Progression of Alzheimer’s Disease

Heidi Jacobs, PhD, an associate investigator at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital and an associate professor of Radiology at Harvard Medical School, is the corresponding author of a new letter in Nature Aging, Spatiotemporal Patterns of Locus Coeruleus Integrity Predict Cortical Tau and Cognition.

Summary:

The locus coeruleus is a small region in the brainstem vulnerable to accumulation of abnormal forms of Alzheimer’s disease-related tau proteins early in adulthood.

But so far, it was not known if accumulation of tau proteins in the locus coeruleus precede spreading of tau to other brain regions and which biological mechanisms contribute to this.

By using specialized in vivo brain scans of older individuals, we showed that changes in the locus coeruleus precede tau increases in other brain regions and together, were associated with future cognitive decline.

This pattern of spreading of tau was associated with genes involved in folding and transport of proteins.

These findings suggest that interventions early in life targeting the locus coeruleus system may contribute to delaying disease progression.

What Question Were You Investigating with this Study?

Autopsy data indicates that the locus coeruleus is one of the first regions to accumulate Alzheimer's disease-related tau pathology, prior to cortical involvement and cognitive changes.

Current in vivo neuroimaging methods do not allow to measure tau pathology directly in the locus coeruleus.

By combining longitudinal information from dedicated magnetic resonance imaging scans visualizing the locus coeruleus, positron emission tomography (PET) of cortical tau pathology and cognitive assessments, we aimed to test the hypothesis that changes in locus coeruleus integrity precede tau accumulation in the cortex.

In addition, we examined whether these routes of pathology spreading is associated with worse cognitive performance.

Finally, as tau spreading occurs in the same way in the majority of the patients with Alzheimer’s disease, we aimed to understand the biological pathways contributing to the tau vulnerability and spreading.

Together, these aims will provide critical information on the spatial and temporal patterns of tau spreading as well as the biological pathways of tau vulnerability and spreading starting in the earliest stages of the disease. In addition, these aims can inform new treatments aimed at halting tau spreading and consequently delaying disease progression.

What Was Your Approach?

We combined three different datasets providing complimentary findings:

1) Data from 77 middle-aged to older individuals from the Harvard Aging Brain Study+ (HABS+). All these individuals underwent multiple MRI-scans, amyloid and tau-PET scans and repeated cognitive assessments. This data set is unique as it includes specialized MRI-scans that can visualize the locus coeruleus and allowed us to examine patterns of tau spreading from the locus coeruleus, and its relationship to cognition.

2) Data from 160 cases from the Rush Memory and Aging Project (MAP): this dataset includes postmortem assessments of the tau pathology in the locus coeruleus among cognitively normal individuals, individuals with mild cognitive impairment and patient with Alzheimer's disease. This dataset was used to validate the patterns of tau spreading that were observed in the HABS dataset.

3) Data from the Allen Human Brain Atlas (AHBA): this is a transcriptional atlas of adult human brains. The information derived from this atlas was used to evaluate potential genetic features underlying the tau spreading patterns observed in the HABS dataset.

What Were the Results?

We found the first human in vivo evidence that lower locus coeruleus integrity precedes tau accumulation in the medial temporal cortex.

Furthermore, this pathway of tau spreading was associated with lower cognitive performance three years later. Once the second type of Alzheimer's disease pathology, beta-amyloid plaques, emerges and increases we see that these cortical tau spreading patterns become more widespread.

This pattern is consistent with disease models stating that beta-amyloid spurs cortical tau pathology.

The biology underlying tau spreading is not well understood, but our data now indicates that these initial patterns of spreading (from the locus coeruleus to the medial temporal cortex) are associated with the biological activity of genes involved in protein transport regulation and protein folding.

What are the Clinical Implications?

These findings confirm the importance of the locus coeruleus as an important marker for detecting risk for Alzheimer's disease earlier than has been feasible so far, and that with these dedicated in vivo and non-invasive MR-images we now have the tools available.

Our findings also hold important implications for interventions, as they indicate that interventions that can support the health of the locus coeruleus-noradrenergic system may be able to mitigate spreading of tau to other regions and cognitive decline.

What’s Next?

The locus coeruleus norepinephrine system is involved in sleep, arousal, stress and mood. In the future, we aim to examine how certain factors can increase the risk of tau spreading or may be able to provide protection.

For example, we have shown that a higher amount of nocturnal awakenings in older individuals is associated with lower locus coeruleus integrity, in particular when tau pathology is elevated. We now aim to examine how sleep can affect tau spreading, and whether locus coeruleus-targeted interventions can improve sleep quality and slow down disease progression.

Similarly, we aim to investigate whether stress or depression increases risk for Alzheimer’s disease, or whether social activity and education can influence these temporal trajectories positively.

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