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Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease
Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE.. Acta neuropathologica communications, 2017-01-21
Topic: Amyloid, tau and blood-test diagnosis
A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Reduced LC neuron numbers were also associated with increased postmortem neuropathology. To examine the cellular and molecular pathogenic processes underlying LC neurodegeneration in aMCI, we performed single population microarray analysis. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI. Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden. Taken together, these observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction. Moreover, they lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.
Key findings
- Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD.
- Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability.
- Reduced LC neuron numbers were also associated with increased postmortem neuropathology.
- These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI.
- Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden.
Why it matters
Postmortem brain tissue showed that loss of nerve cells in the locus coeruleus occurred early, during the transition from no cognitive impairment to mild cognitive impairment, and was linked to worse cognitive function. This identifies an early site of damage but does not offer a treatment or cure.
Study details
- Evidence strengthLow
How this study scored 49/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Acta neuropathologica communications) |
| Journal's citation record | 1 / 4 | Acta Neuropathologica Communications: journal h-index 129 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 284 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.8 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 4 / 6 | Cited 13.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 3 / 4 | Cited 88 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Scott Counts: h-index 47 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | New York University: institution h-index 1,612 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28109312) |
| Free to read | 2 / 2 | Free to read |
| Total | 49 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s40478-017-0411-2
- PubMed: 28109312
- Original source →
- Free full text: Acta Neuropathologica Communications →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Kelly, S. C., He, B., Perez, S. E., Ginsberg, S. D., Mufson, E. J., & Counts, S. E. (2017). Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta neuropathologica communications. https://doi.org/10.1186/s40478-017-0411-2
Vancouver
Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE. Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta neuropathologica communications. 2017. doi:10.1186/s40478-017-0411-2. PMID: 28109312.
BibTeX
@article{kelly2017-28109312,
author = {Kelly, S. C. and He, B. and Perez, S. E. and Ginsberg, S. D. and Mufson, E. J. and Counts, S. E.},
title = {{Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease}},
journal = {Acta neuropathologica communications},
year = {2017},
doi = {10.1186/s40478-017-0411-2},
pmid = {28109312},
url = {https://doi.org/10.1186/s40478-017-0411-2}
}
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