Relationship between plaques, tangles, and loss of cortical cholinergic fibers in alzheimer disease
Abstract
Recent observations in our laboratory have indicated substantial and systematic regional variations in the loss of cortical cholinergic fibers in Alzheimer disease (AD). Previous attempts to study the relationship between cortical cholinergic loss and the density of cortical pathological lesions have resulted in conflicting findings. Furthermore, most reports have correlated density of plaques and tangles with the residual level of cholinergic innervation rather than its loss. The purpose of the present study was to determine the relationship between loss of cholinergic axons and density of tangles and beta-amyloid (Abeta) deposits in various cortical areas of AD brains. Abeta deposits and tangles were observed throughout the cerebral cortex. Quantitative analysis revealed almost no correlation between loss of cholinergic fibers and the density of Abeta deposits. Qualitative observations revealed similar results when cored and neuritic plaques were considered separately. By contrast, cholinergic fiber loss displayed a significant correlation with the density of tangles (r = 0.52-0.79). However, in a few areas, such as the cingulate cortex, tangle density appeared to be unrelated to the loss of cholinergic fibers. These results indicate that cortical cholinergic denervation in AD is related to cytoskeletal pathology. However, the lack of a perfect relationship with cytoskeletal pathology implicates additional factors in the cholinergic pathology of AD.
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Cholinergic degeneration is a major clinical feature of both age-related cognitive decline and Alzheimer's dementia.
“with cholinergic degeneration a major clinical feature of both age-related cognitive decline and Alzheimer’s dementia [16,17].”
From Systematic Overview of Bacopa monnieri (L.) Wettst. Dominant Poly-Herbal Formulas in Children and Adolescents (2017) · cites this paper as [17]
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ResultSelf-citationHuperzine A and Its Neuroprotective Molecular Signaling in Alzheimer’s Disease
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Self-citationComparative distribution of tau phosphorylated at Ser262 in pre-tangles and tangles
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“The cholinergic fiber loss displays a significant correlation with the density of neurofibrillary tangles in the cerebral cortex.(2) The cause of sporadic AD is unknown.”
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“Although the Ab plaque density in these and other cortical regions does not directly relate to the absolute amount of degenerated cholinergic axons, it correlates significantly with the number of remaining fibers and with the percentage of lost fibers (Geula et al., 1998).”
Boundy, K. L., Barnden, L. R., Katsifis, A. G., & Rowe, C. C. (2005) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2004.06.012 · Cited by 17 · see citing works
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BackgroundNerve Growth Factor Differentially Affects Spatial and Recognition Memory in Aged Rats
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“vation in the cerebral cortex is universally accepted as a major aspect of advanced AD [16–18].”
Shades of gray in human white matter
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“[37] the nucleus basalis is not a site of particularly prominent amyloid deposition and there is no correlation between plaque density and severity of cholinergic axonal loss in cortical areas.”
Colloby, S. J., McKeith, I. G., Wyper, D. J., O'Brien, J. T., & Taylor, J. (2015) · Journal of Neurology · doi:10.1007/s00415-015-7827-z · Cited by 12 · see citing works
“The basal forebrain is affected in established Alzheimer’s disease (AD), with a robust loss of cholinergic neurons, including those innervating the hippocampus and cortex [2, 6, 14, 45, 52], and consequent reductions in acetylcholine have been observed in hippocampal, temporal, frontal and parietal areas [19, 37] with…”
BackgroundPathological Diagnosis of Alzheimer’s Disease
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Self-citationAssociation of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer’s Disease
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“In a neuropathological study, there was almost no correlation between the loss of cholinergic fibers and the density of A (cid:2) deposits [35].”
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Neuropathologie und biologische Marker degenerativer Demenzen
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The first 25 years of the Northwestern University SuperAging Program
Weıntraub, S., Gefen, T. D., Geula, C., & Mesulam, M. M. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70312 · Cited by 7 · see citing works
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- Authors
- Geula, C., Mesulam, M. M., Saroff, D. M., & Wu, C.-K.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Northwestern University (US)
- Corresponding author
- Geula, Changiz
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1998-01
- Volume
- 57
- Issue
- 1
- Pages
- 63-75
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W2092211788
- Cited by
- 102
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 10282, R29AG010282)
- 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, neurofibrillary tangles, amyloid plaques, neuritic plaques, regional variation, cholinergic innervation
- MeSH terms
- Aged, Alzheimer Disease, Cerebral Cortex, Choline O-Acetyltransferase, Fluorescent Dyes, Humans, Nerve Fibers, Organ Specificity, Reference Values, Regression Analysis, Thiazoles, Amyloid beta-Peptides, Neurofibrillary Tangles, Benzothiazoles, Plaque, Amyloid
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