Systematic Regional Variations in the Loss of Cortical Cholinergic Fibers in Alzheimer's Disease
Abstract
The loss of cortical cholinergic fibers in Alzheimer's disease was investigated using choline acetyltransferase immunohistochemistry and acetylcholinesterase histochemistry. Within both the normal and Alzheimer's cerebral cortex, the two methods revealed an identical pattern of fiber staining. In the normal brain, cholinergic fiber density was highest in limbic and paralimbic cortical zones, intermediate in most sensory-motor and association zones, and lowest within the primary visual and visual association areas of the occipital lobe. In general, supragranular cortical layers contained a higher density of cholinergic fibers, and most of these were oriented vertically. In Alzheimer's disease, an overall 55% loss of cortical cholinergic fibers was detected. There was, however, marked regional variations in the extent of this loss in different cortical areas. Cortical areas within the temporal lobe, particularly the temporal association areas, displayed a dramatic loss of cholinergic fibers. By contrast, the anterior cingulate cortex, primary visual, primary somatosensory, and primary motor cortex displayed a relative preservation of cholinergic fibers. As a whole, greater loss of cholinergic fibers was detected in supragranular layers and in fibers oriented vertical to the cortical surface. These results indicate that cholinomimetic therapies are likely to have different effects on cholinergic transmission in various cortical areas. The precise mechanisms that lead to the regional variations in cortical cholinergic denervation in Alzheimer's disease remain to be elucidated.
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There is a high degree of cholinergic fiber loss in primary auditory and inferior frontal cortices.
“where there is a high degree of cholinergic fiber loss. 41”
From Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity (2025) · cites this paper as [41]
The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.
“The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.233”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [233]
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InfluentialLi, W., Howard, J. D., & Gottfried, J. A. (2010) · Brain · doi:10.1093/brain/awq209 · Cited by 140 · see citing works
“…discrimination in piriform cortex (Hasselmo et al., 1992; Saar et al., 2001; Wilson, 2001), our results would be consistent with the profound perturbation of cholinergic innervation to the medial temporal lobes that is a hallmark of Alzheimer’s disease (Geula and Mesulam, 1996; Mesulam, 2004).”
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Nerve growth factor metabolic dysfunction in Alzheimer's disease and Down syndrome
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“Frontal, parietal, and hippocampal cortex as well as the posterior cingulate cortex showed a modest depletion of cholinergic transmission whereas the least impairment was found in the visual cortex and the anterior cingulate cortex (Emre et al., 1993; Geula and Mesulam, 1996).”
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“In this framework, AD would be not characterized by a diffuse impairment of the cholinergic systems since brainstem cholinergic innervation of the thalamus was relatively spared (Mash et al., 1985; Geula and Mesulam, 1989, 1996, 1999; Mesulam, 2004).”
APOE-related biomarker profiles in non-pathological aging and early phases of Alzheimer's disease
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“In other cortical areas (primary motor, premotor and cingulate), the fibre loss was less pronounced ( 45%) (Geula and Mesulam, 1996).”
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“[19] Hence, AD may be best characterized not by general cholinergic neuronal loss but rather by selective cholinergic denervation of the cerebral cortex, most severely in the temporal lobes and in the adjacent paralimbic areas.[9]”
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“While it is generally co-localized with AChE in cholinergic neurons in normal ageing and Alzheimer’s disease (Mesulam and Geula, 1992; Geula and Mesulam, 1996), it has been found to be increased in MCI due to Alzheimer’s disease in the hippo- campus and frontal lobe (DeKosky et al., 2002;…”
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“In contrast, brainstem cholinergic innervation of the thalamus would be relatively spared in AD [26–29].”
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“In contrast, brainstem cholinergic innervation of the thalamus would be relatively spared in AD [Geula and Mesulam, 1989, 1996, 1999; Mesulam et al., 2004].”
BackgroundSomatosensory responses in normal aging, mild cognitive impairment, and Alzheimer’s disease
Stephen, J. M., Montaño, R., Donahue, C. H., Adair, J. C., Knoefel, J. E., Qualls, C., Hart, B. L., Ranken, D. M., & Aine, C. J. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0343-5 · Cited by 74 · see citing works
“Based on previous literature, we hypothesized that primary somatosensory cortex would be relatively spared in mild cognitive impairment (MCI) and AD (Geula and Mesulam 1996; Teipel et al. 2007), but that secondary somatosensory cortices (SII) may be affected since association cortices have been reported to be affected…”
Kus, L., Borys, E., Chu, Y. P., Ferguson, S. M., Blakely, R., Emborg, M. E., Kordower, J. H., Levey, A. I., & Mufson, E. J. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10759 · Cited by 73 · see citing works
“These findings are in line with other immunohistochemical observations showing a lack of cholinergic neurons in these regions in the monkey and human cortex (Mesulam et al., 1986; Mufson et al., 1989a; Geula and Mesulam, 1996; Wu et al., 2000; Lopez-Gimenez et al., 2002).”
BackgroundResultAmyloid precursor protein-induced axonopathies are independent of amyloid-β peptides
Stokin, G. B., Almenar-Queralt, A., Gunawardena, S., Rodrigues, E. M., Falzone, T., Kim, J., Lillo, C., Mount, S. L., Roberts, E. A., McGowan, E., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn240 · Cited by 72 · see citing works
“Density of ChAT-IR fibers was approximated with a Weibel grid using an intersection approach ( 78 ,79).”
MethodSarter, M. F. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00003-4 · Cited by 70 · see citing works
Meta‐analysis of functional imaging data using replicator dynamics
Neumann, J., Lohmann, G., Derrfuß, J., & von Cramon, D. Y. (2005) · Human Brain Mapping · doi:10.1002/hbm.20133 · Cited by 70 · see citing works
Piggott, M. A., Owens, J., O'Brien, J. T., et al. (2003) · Journal of Chemical Neuroanatomy · doi:10.1016/s0891-0618(03)00002-4 · Cited by 68 · see citing works
Implicit memory for music in Alzheimer's disease.
Halpern, A. R., & O’Connor, M. G. (2000) · Neuropsychology · doi:10.1037/0894-4105.14.3.391 · Cited by 68 · see citing works
Imaging of Cholinergic and Monoaminergic Neurochemical Changes in Neurodegenerative Disorders
Bohnen, N. I., & Frey, K. A. (2007) · Molecular Imaging and Biology · doi:10.1007/s11307-007-0083-6 · Cited by 67 · see citing works
“[C-11]PMP and [C-11]MP4A AChE radioligand studies have reported in vivo reductions of cortical AChE activity that were strikingly less than expected on the basis of postmortem data [28, 29, 116, 117].”
BackgroundAlzheimer's disease-related synapse loss in the cingulate cortex
Scheff, S. W., & PRICE, D. A. (2001) · Journal of Alzheimer s Disease · doi:10.3233/jad-2001-3509 · Cited by 66 · see citing works
“lamina III showing a greater loss than lamina V [21].”
Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease
Cullen, K. M., Halliday, G. M., Double, K. L., Brooks, W. S., Creasey, H. M., & Broe, G. A. (1997) · Neuroscience · doi:10.1016/s0306-4522(96)00569-6 · Cited by 64 · see citing works
Mohamed, L. A., Keller, J. N., & Kaddoumi, A. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.01.013 · Cited by 63 · see citing works
“According to the cholinergic hypothesis of AD, loss of cognitive function is largely attributed to depletion of cholinergic neurotransmitters such as acetylcholine (ACh) mainly in the cerebral cortex and caudate nucleus [4, 5].”
BackgroundResultBabiloni, C., Squitti, R., Percio, C. D., Cassetta, E., Ventriglia, M. C., Ferreri, F., Tombini, M., Frisoni, G. B., Binetti, G. G., Gurzì, M., et al. (2007) · Clinical Neurophysiology · doi:10.1016/j.clinph.2007.03.016 · Cited by 63 · see citing works
Hall, H., Iulita, M. F., Gubert, P., Aguilar, L. F., Ducatenzeiler, A., Fisher, A., & Cuello, A. C. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.11.009 · Cited by 62 · see citing works
“Based on the prominent loss of cortical cholinergic innervation in AD brains [2,42,43] and the correlation between cognitive deficits and cholinergic abnormalities [4], current symptomatic treatments for AD rely for the most part on AChE-I to increase cholinergic tone.”
BackgroundBabiloni, C., Frisoni, G. B., Pievani, M., Vecchio, F., Infarinato, F., Geroldi, C., Salinari, S., Ferri, R., Fracassi, C., Eusebi, F., et al. (2007) · Human Brain Mapping · doi:10.1002/hbm.20467 · Cited by 60 · see citing works
“…[Babiloni et al., 2004a; Dierks et al., 1993, 2000; Huang et al., 2000; Mesulam et al., 2004; Moretti et al., 2004; Rodriguez et al., 1999a,b], but a relatively spared thalamic cholinergic innervations from the brainstem [Geula and Mesulam, 1989, 1996, 1999; Mash et al, 1985; Mesulam et al., 2004].”
BackgroundReceptors for pro‐resolving mediators are increased in Alzheimer's disease brain
Emre, C., Hjorth, E., Bharani, K., Carroll, S., Granholm, A., & Schultzberg, M. (2020) · Brain Pathology · doi:10.1111/bpa.12812 · Cited by 60 · see citing works
“Cholinergic neurons in BF degenerate in the early stages of AD and are strongly associated with the deterioration of cognitive processes (26).”
BackgroundWhite-matter vascular lesions correlate with alpha EEG sources in mild cognitive impairment
Babiloni, C., Frisoni, G. B., Pievani, M., Toscano, L., Percio, C. D., Geroldi, C., Eusebi, F., Miniussi, C., & Rossini, P. M. (2008) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2008.03.021 · Cited by 57 · see citing works
“Whereas, brainstem cholinergic innervation of the thalamus would be relatively spared (Geula & Mesulam, 1989, 1996, 1999; Mash, Flynn, & Potter, 1985; Mesulam et al., 2004).”
Sihver, W., Gillberg, P.-G., Svensson, A., & Nordberg, A. K. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00295-x · Cited by 53 · see citing works
Babiloni, C., Frisoni, G. B., Vecchio, F., Lizio, R., Pievani, M., Geroldi, C., Fracassi, C., Vernieri, F., Rodriguez, G., Nobili, F. M., et al. (2010) · Human Brain Mapping · doi:10.1002/hbm.21157 · Cited by 50 · see citing works
“Instead, brainstem cholinergic innervation of the thalamus would be relatively spared [Geula and Mesulam, 1989, 1996, 1999; Mash et al., 1985; Mesulam et al., 2004].”
BackgroundSensory processing deficits and related cortical pathological changes in Alzheimer’s disease
Zhang, N. K., Zhang, S. K., Zhang, L. I., Tao, H. W., & Zhang, G.-W. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1213379 · Cited by 49 · see citing works
“Degeneration of cholinergic fibers in the visual cortex is not conclusive, as no deficit (Geula and Mesulam, 1996) and large depletion (Beach et al.”
BackgroundObject and Action Naming in Alzheimer's Disease
Williamson, D. J. G., Adair, J. C., Raymer, A. M., & Heilman, K. M. (1998) · Cortex · doi:10.1016/s0010-9452(08)70517-3 · Cited by 47 · see citing works
Changes in brain functional homogeneity in subjects with Alzheimer's disease
Volkow, N. D., Zhu, W., Felder, C. A., Mueller, K. D., Welsh, T. F., Wang, G., & de Leon, M. J. (2001) · Psychiatry Research Neuroimaging · doi:10.1016/s0925-4927(01)00130-5 · Cited by 49 · see citing works
Dubelaar, E. J. G., Verwer, R. W. H., Hofman, M. A., van Heerikhuize, J. J., Ravid, R., & Swaab, D. F. (2004) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/63.2.159 · Cited by 45 · see citing works
“Changes reported are decreased acetyl-cholinesterase activity in the cerebral cortex and decreased choline acetyltransferase (ChAT) activity in the amygdala, hippocampus, and cortex (2), reduced ChAT activity and acetyl-cholinesterase-positive fibers in the frontal, parietal, temporal, and visual cortices (3), and a b…”
BackgroundShah, P., Lal, N., Leung, E., Traul, D., Gonzalo‐Ruiz, A., & Geula, C. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090937 · Cited by 45 · see citing works
“We have previously shown that in the primate brain, acetylcholinesterase (AChE) activity specifically visualizes cortical cholinergic axons.(38,39) Therefore, we used AChE histochemistry for determination of the status of these axons.”
Self-citationAznavour, N., Watkins, K. C., & Descarries, L. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20501 · Cited by 45 · see citing works
Nicotine increases brain functional network efficiency
Wylie, K. P., Rojas, D. C., Tanabe, J., Martín, L., & Tregellas, J. R. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.06.079 · Cited by 44 · see citing works
“The temporal pole, insula, orbitofrontal cortex and hippocampus are all atrophied and show decreases in cholinergic fibers (Geula and Mesulam, 1996; Halliday et al., 2003).”
BackgroundAutomated measurement of nerve fiber density using line intensity scan analysis
Sathyanesan, A. G., Ogura, T., & Lin, W. (2012) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2012.02.019 · Cited by 44 · see citing works
“…fiber density upon the onset or development of neurodegenerative diseases, such as Alzheimer’s (Boncristiano et al., 2002; Bronfman et al., 2000; Geula and Mesulam, 1996; Ikonomovic et al., 2007; Wong et al., 1999) and Parkinson’s (Jellinger et al., 1991; Kuhl et al., 1996) as well as…”
BackgroundMethodMuscarinic acetylcholine receptors activate the acetylcholinesterase gene promoter
Nitsch, R. M., Rossner, S., Albrecht, C., Mayhaus, M., Enderich, J., Schliebs, R., Wegner, M., Arendt, T., & von der Kammer, H. (1998) · Journal of Physiology-Paris · doi:10.1016/s0928-4257(98)80029-6 · Cited by 44 · see citing works
Mieling, M., Meier, H., & Bunzeck, N. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105393 · Cited by 41 · see citing works
Groussard, M., Chan, T. G., Coppalle, R., & Platel, H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180474 · Cited by 40 · see citing works
“To account for this result, they suggest an impairment of aesthetic auditory appreciation ability caused by advanced neural degeneration in the auditory cortex, when compared to the primary visual cortex [54–56].”
Cortical cholinergic denervation in primary progressive aphasia with Alzheimer pathology
Mesulam, M. M., Lalehzari, N., Rahmani, F., Ohm, D. T., Shahidehpour, R. K., Kım, G., Gefen, T. D., Weıntraub, S., Bigio, E. H., & Geula, C. (2019) · Neurology · doi:10.1212/wnl.0000000000007247 · Cited by 39 · see citing works
Self-citationAdvances on the Understanding of the Origins of Synaptic Pathology in AD
Lacor, P. N. (2007) · Current Genomics · doi:10.2174/138920207783769530 · Cited by 38 · see citing works
“AD synapse pathology begins with a slight loss of synapses resulting from cholinergic and glutamatergic deafferentation [168,169], which is then accompanied by a decrease in the number of dendritic spines.”
BackgroundKrenz, I., Kalkan, D., Wevers, A., de Vos, R. A. I., Steur, E. N. H. J., Lindstrom, J. M., Pilz, K., Nowacki, S., Schütz, U., Moser, N., et al. (2001) · Journal of Chemical Neuroanatomy · doi:10.1016/s0891-0618(01)00112-0 · Cited by 37 · see citing works
Orta‐Salazar, E., Cuellar-Lemus, C. A., Díaz-Cintra, S. Y., & Feria‐Velasco, A. (2014) · Neurología (English Edition) · doi:10.1016/j.nrleng.2012.10.010 · Cited by 36 · see citing works
- Authors
- Geula, C., & Mesulam, M.-M.
- Affiliations
- Harvard University (US)
- Northwestern University (US)
- Corresponding author
- Geula, Changiz
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 1996
- Volume
- 6
- Issue
- 2
- Pages
- 165-177
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- OpenAlex
- W1964729801
- Cited by
- 202
- References
- 0
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 7 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 5 · 2013: 8 · 2012: 6
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-08812, AG 10282, R29AG010282, P50AG005134, AG 05134)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, cholinergic denervation, regional variation, choline acetyltransferase, acetylcholinesterase, temporal lobe, limbic cortex
- MeSH terms
- Aged, Alzheimer Disease, Cerebral Cortex, Cholinergic Fibers, Female, Hippocampus, Humans, Male, Middle Aged, Tissue Distribution
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