Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early‐stage biomarker discovery
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Introduction: Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). Methods: The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. Results: As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age‐related changes spare the LC. Discussion: The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage‐wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high‐yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages.
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In Alzheimer's disease, neuron loss extent does not correlate with neurofibrillary tangle extent; tangles occur in normal brain and there is a long delay between tangles and neuronal death.
“Yet the extent of neuron loss is not correlated with the extent of neurofibrillary tangles; tangles are present in normal brain and there is a long delay between the appearance of tangles and the onset of neuronal death (252, 251, 253).”
From Chemiexcitation: Mammalian Photochemistry in the Dark<sup>†</sup> (2023) · cites this paper as [252]
The Discussion reports a long gap between tau pathology and significant neuronal loss in the locus coeruleus, and says tangles are not always a surrogate for neuronal loss. The Results describe cognitively normal individuals at Braak stage I, consistent with tangles occurring without dementia. The paper does not establish the broader, categorical claim that the extent of neuronal loss is uncorrelated with the extent of tangles throughout Alzheimer’s disease. (LLM, conf=0.86)
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- Authors
- Theofilas, P., Ehrenberg, A. J., Dunlop, S., Di Lorenzo Alho, A. T., Nguy, A., Leite, R. E. P., Rodriguez, R. D., Mejia, M. B., Suemoto, C. K., Ferretti-Rebustini, R. E. D. L., Polichiso, L., Nascimento, C. F., Seeley, W. W., Nitrini, R., Pasqualucci, C. A., Jacob Filho, W., Rueb, U., Neuhaus, J., Heinsen, H., & Grinberg, L. T.
- Affiliations
- University of California, San Francisco (US)
- Hospital Albert Einstein São Paulo Brazil
- Department of Pathology, LIM-22 University of São Paulo Medical School São Paulo Brazil
- Universidade de São Paulo (BR)
- Division of Geriatrics University of Sao Paulo Medical School São Paulo Brazil
- University of São Paulo, School of Nursing São Paulo Brazil
- Department of Neurology University of Sao Paulo Medical School São Paulo Brazil
- Goethe University Frankfurt (DE)
- Corresponding author
- Grinberg, Lea T.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-08-08
- Volume
- 13
- Issue
- 3
- Pages
- 236-246
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC5298942
- OpenAlex
- W2513816257
- Cited by
- 416
- References
- 62
- Citations by year
- 2026: 38 · 2025: 60 · 2024: 53 · 2023: 55 · 2022: 56 · 2021: 55 · 2020: 34 · 2019: 24 · 2018: 22 · 2017: 19
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01AG040311)
- Sociedade Beneficente Israelita Brasileira Albert Einstein
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, locus coeruleus
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Female, Humans, Locus Coeruleus, Male, Middle Aged, Neurons, Stereotaxic Techniques, Biomarkers, Disease Progression
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