When Tau Wanders Off, Subcortical Axon Firing Goes Mum

Series - Human Amyloid Imaging 2025:

When it comes to tau tangles, cortical deposits receive the lion’s share of scientists’ attention, but it is the tiny subcortical regions where tangles originate that might set the course for Alzheimer's. New data presented at the Human Amyloid Imaging conference, held January 15-17 in San Juan, Puerto Rico, suggests as much. Researchers say that connectivity among the white-matter tracts linking the locus coeruleus to other brain regions determines how well these systems can compensate for one another’s functions and offset the effects of neuronal death in the early stages of Alzheimer's disease.

  • Tangles appear in the locus coeruleus before spreading to the cortex
  • The amount of connectivity between the LC and other subcortical nuclei may affect tau pathology and disease progression.
  • Might stimulating subcortical nuclei slow cognitive decline?

The locus coeruleus—with its two lobes the size of a grain of rice in our brainstems—serves as a hub that drives brain-wide functions such as the sleep-wake cycle. It’s also considered the birthplace of tau pathology. Autopsy data suggests that tangles accumulate in the LC before they fan out into the medial temporal lobe (Ehrenberg et al., 2017). This spreading process seems to be a one-way street: Neurodegeneration in the LC accelerates tau spread, but high levels of tangles in the medial temporal lobe don’t disrupt the LC (May 2024 news).

Studying how tau in the LC affects pathology and cognitive function in living people, however, has proven extraordinarily challenging. Not only is the LC too small to see on most scanners, but all available tau PET tracers have off-target binding to neuromelanin and ferromagnetic materials throughout this region. “Everything we do in the locus coeruleus is a proxy,” Heidi Jacobs of Massachusetts General Hospital, Boston, told Alzforum.

At HAI, Jacobs and colleagues presented alternative methods for measuring how tau affects subcortical networks, particularly these regions’ ability to help one another out when neurons begin to die during Alzheimer's. In one poster, Yuliya Patsyuk, Maastricht University, Netherlands, used 7T diffusion MRI scanning in 47 cognitively unimpaired people to measure microstructural integrity in the tracts connecting the LC to other brain regions.

Spot the Dot? 7T diffusion MRI scans show that the fiber tract (red) connecting the locus coeruleus (arrow to blue) to the entorhinal cortex (yellow) is among first to break down as plasma tau levels increase. (Courtesy of the Jacobs lab.)

Patsyuk found that people with worse diffusion within the tract connecting the LC to the entorhinal cortex (EC), and less structural integrity, tended to have higher plasma levels of phosphorylated tau species and of the astroglial activation marker GFAP. The result implies a link between white matter breakdown, tau aggregation and neuroinflammation.

The pattern seemed specific to the LC-EC tract. The fibers connecting the LC and prefrontal cortex did not show the same associations between microstructural integrity and pTau blood biomarker levels. This suggests that the LC-EC tract is particularly vulnerable to break down even before other pathologies appear and supports the idea that tau pathology moves via anatomical connections (Feb 2018 news).

Similarly, Elouise Koops, MGH, found worse LC-EC tract degradation and higher levels of entorhinal tangles in women from the COLBOS cohort of people who carry the PSEN1 Paisa mutation. Although none of the participants had yet developed dementia, mutation carriers whose LC-EC tracts contained scant fibers did worse on memory tests compared to those with denser connections. Members of the kindred who don’t carry the mutation showed no link between tract density and performance.

Tau Versus Fiber Tracts. Among asymptomatic PSEN1 E280A mutation carriers (dark blue), those with more tangles in the entorhinal cortex had thinner fibers connecting the LC and EC . This was not true for but not non-carriers (light blue). (Courtesy of the Jacobs lab.)

Patsyuk does not know whether white-matter degradation follows tau accumulation or whether a breakdown in fiber microstructure allows tau to spread more easily. For that, she told Alzforum, the team will need longitudinal data, which they hope to acquire soon.

Because the LC and other subcortical systems, such as the hypothalamus and Raphe nuclei, are so highly interconnected with one another, and with the rest of the brain for control of brain-wide functions, Jacobs believes they can likely compensate for each other to a degree when one begins to lose neurons in the early stages of Alzheimer's. For instance, the LC’s ability to regulate arousal via norepinephrine release might be able to mask neuronal loss in the hypothalamus that would otherwise affect sleep. But once the LC begins losing neurons, too, the functional loss becomes more severe, Jacobs said.

This compensatory ability may affect cognition too. Lukas Heinrich, MGH, used fMRI to record functional connectivity between the LC and the medial temporal lobe in 128 people from the HABS cohort while they were performing a memory test. Those with higher cognitive reserve—calculated as a combination of education level, IQ, and occupation—at baseline outperformed those with lower reserve regardless of whether they had brain amyloid in the neocortex.

People with high connectivity between the LC and medial temporal lobe continued performing well over the course of about seven years even if they accumulated amyloid elsewhere in the brain, suggesting these strong connections could delay the impact of plaques on cognition. Emma Wiklund, MGH, found similar patterns when she studied the LC’s glucose metabolism using FDG-PET. People with more metabolic activity in the LC, she found, performed more consistently on cognitive tests over the course of seven years regardless of their overall brain levels of plaques or tangles.

Saving Grace. Strong functional connectivity between the LC and MTL slowed the rate of cognitive decline in people with high amyloid loads (measured by PiB-PET) and high cognitive reserve scores (CR). (Courtesy of the Jacobs lab.)

Melissa Murray, Mayo Clinic, Jacksonville, Florida, said the results make sense to her. Practicing a skill builds connections between brain regions, hence the idea that education builds a strong white matter “highway” between the locus coeruleus and other brain regions could help explain why it is protective in Alzheimer's disease. Murray was impressed by the methods the Jacobs lab has developed to study the LC, despite the challenges of imaging this area. “A lot of people just kind of move past it because it's a minefield,” she told Alzforum.

Jacobs acknowledged that no one has yet been able to show definitive longitudinal data that would prove whether and how tau spreads from the LC to the entorhinal cortex. If the hypothesis holds true, she said, “maybe we can find ways to halt tau propagation and delay disease progression.”

Lea Grinberg, University of California, San Francisco, told Alzforum she is glad scientists are paying more attention to the locus coeruleus. “People are starting to link the dots,” she said. Evidence from Grinberg’s lab suggests that some neurons and nuclei are more vulnerable to tau and other pathologies than are their neighbors, although why is a mystery. “If we can understand this, we can create neuroprotective therapeutics,” she said. Examples include atomoxetine, an ADHD treatment targeting norepinephrine transporters that has improved brain metabolism in an Alzheimer's repurposing trial. A recent proteomics study suggested atomoxetine might boost norepinephrine in the LC (Sep 2024 news).

Jacobs’ group is exploring a different therapeutic approach. They are testing whether stimulating the LC can slow cognitive decline. In a recently started clinical trial called WALLe, clinicians stimulate the LC and nearby nuclei by attaching electrodes to a participant’s ear, near the spot where the vagus nerve terminates, and apply electrical current to it. This is an application of transcutaneous auricular vagus never stimulation (Kim et al., 2022).

Hear the Shocker? The WALLe trial is testing in cognitively normal volunteers whether stimulating the vagus via an electrode placed on the outer ear will trigger norepinephrine release in the locus coeruleus and, in this way, benefit memory and neuroinflammation. (Courtesy of the Jacobs lab.)

So far, the trial has enrolled 98 cognitively unimpaired older people who receive this stimulation for about 20 minutes per day over the course of two weeks. The researchers are testing whether this approach affects performance on a face-name memory test, a cognitive composite score, and markers of inflammation. They will monitor changes in brain structure via 7T MRI over the course of four months.

An older, more invasive approach, deep-brain stimulation, is effective in Parkinson’s disease (Jan 2013 news). Can tickling the vagus nerve in this way help cognition? Stay tuned.—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

News Citations

  1. More Evidence that Locus Coeruleus Demise Precedes Cortical Tangles
  2. Imaging Clinches Causal Connections between Aβ, Tau, Circuitry, and Cognition
  3. CSF Proteomics Hints at How ApoE4 Promotes AD, and How a Drug Hinders It
  4. A Day in the OR: Surgeons Zap Neurons for Parkinson’s, AD

Therapeutics Citations

  1. Atomoxetine

Paper Citations

  1. Ehrenberg AJ, Nguy AK, Theofilas P, Dunlop S, Suemoto CK, Di Lorenzo Alho AT, Leite RP, Diehl Rodriguez R, Mejia MB, Rüb U, Farfel JM, de Lucena Ferretti-Rebustini RE, Nascimento CF, Nitrini R, Pasquallucci CA, Jacob-Filho W, Miller B, Seeley WW, Heinsen H, Grinberg LT. Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease. Neuropathol Appl Neurobiol. 2017 Aug;43(5):393-408. Epub 2017 Mar 31 PubMed.
  2. Kim AY, Marduy A, de Melo PS, Gianlorenco AC, Kim CK, Choi H, Song JJ, Fregni F. Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Sci Rep. 2022 Dec 21;12(1):22055. PubMed.

External Citations

  1. WALLe

Further Reading

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