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Inflammation, Aβ Deposition, and Neurofibrillary Tangle Formation as Correlates of Alzheimer's Disease Neurodegeneration
Abstract
We evaluated entorhinal cortex and superior frontal gyrus for hallmarks of Alzheimer's disease (AD) pathology, including inflammation, in three patient sets: AD patients, nondemented elderly patients with few or no neurofibrillary tangles (NFTs) and amyloid β peptide (Aβ) deposits, i.e. normal controls (NC), and nondemented elderly patients with profuse entorhinal cortex NFTs and neocortical Aβ deposits, i.e. high pathology controls (HPC). Membrane attack complex (C5b-9) immunoreactivity and immune activation of microglia (MHCII expression) were used as general markers for inflammation. Compared to NC patients, AD patients exhibited significant cortical synapse loss, Aβ deposition, NFT formation, and inflammation. HPC patients also had significantly elevated Aβ deposition and NFT formation, but there was no evidence of synapse loss and little or no evidence of inflammation. Across patients and brain regions the measures of inflammation each accounted for significant percentages of the variance in synaptophysin immunoreactivity and each was more highly correlated with synapse estimates than NFT formation or Aβ deposition.
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“Increased MHCII staining, counts or expression was noted in: the entorhinal cortex,7, 18, 20, 35, 43, 47 frontal and temporal gyri,7, 19, 24, 32, 33, 39, 45, 56 hippocampus20, 25, 27, 30, 32, 33, 34, 35, 36, 37, 38, 40, 42, 43, 44, 47 and frontal,18, 21, 25, 40, 41, 44, 46, 48, 49, 52 temporal16, 17, 18, 28, 30, 35, 43, 44, 48, 52 and occipital cortices.25, 35, 41, 43, 44”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“major histocompatibility complex II (36/43 studies)”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
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“Nearly identical results were obtained in our previous research with six other HPC patients.5”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
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In the citing paper
“Elevations in neuroinflammatory markers are widely reported in Alzheimer’s disease (AD), both in animal models1, 2, 3 and human subjects.4, 5, 6, 7”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
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“Five of these studies reported higher levels of microglia markers in AD, three using HLA-DR,7, 33, 40 one using CD68,83 and one using both TREM2 and Iba1.61”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
In the citing paper
“As in our previous research, 5 counts of the various elements at ϫ100 final magnification were recorded by an observer blind to disease state.”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
In the citing paper
“We have also found that HPC patients show little or no evidence of neocortical or limbic synapse loss, 5 underscoring the critical relationship of neuritic degeneration to dementia.”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
In the citing paper
“As in our previous study, 5 HPC patients had significantly higher (Ͼ36%) synaptophysin immunoreactivity on Western blot analysis compared with AD patients (F 1,14 ϭ 25.8, P Ͻ 0.0003), whereas they did not differ from ND patients on this measure (F 1,14 ϭ 1.9, P Ͼ 0.50, 7% difference; Table 1).”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
In the citing paper
“Similar results on brain regional changes in AD pathology were obtained in our previous study of ND, HPC, and AD patients.5”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
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Research works printed but not linked: 21
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Self-citationCerebrospinal Fluid Cytokine Dynamics Differ Between Alzheimer Disease Patients and Elderly Controls
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“important etiological and pathophysiological factors leading to dementia and Alzheimer’s disease [28,29].”
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“Moreover, some patients with high plaque burden exhibit no dementia [29] and also demonstrate almost no evidence of neuroinflammation or neurodegeneration [30].”
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“In demented >90year-old individuals, a decrease in the synaptophysin in the frontal cortex was found, while in cognitively impaired non-demented individuals, an increase in the expression of synaptophysin was seen [40].”
BackgroundResultSummers, K. L., Schilling, K. M., Roseman, G. P., Markham, K. A., Dolgova, N. V., Kröll, T., Sokaras, D., Millhauser, G. L., Pickering, I. J., & George, G. N. (2019) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.9b00507 · Cited by 42
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“There are numerous reports of significant neuroinflammation in AD in which cell damage and death are thought to occur as the result of inflammation [34].”
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“In agreement with an antiinflammatory role of Aβ peptides [32] there was less neuroinflammation in high-pathology non-demented individuals [90-92].”
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“Despite multiple studies showing the presence of neurofibrillary tangles in the absence of A β deposition [8].”
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“For high-pathology control patients, complement and microglial activations were comparable to NC levels and were significantly better than AD levels [40].”
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“Specifically, NDAN individuals show little or no synapse loss [16], along with preserved neurogenesis potentially regulated by microRNAs [17], as well as PSDs that present with a unique proteomic signature [18] and are resistant to Aβ oligomer binding [19], thus protecting synapses from Aβ oligomer–driven dysfunction…”
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“Systems which we would classify as triggered by external factors are any that involve infection, such as acquired prion disease (aggregation is initiated by the introduction of an infectious prion), but also those proposed models in which bacterial infections trigger neurodegenerative disease, or in which inflammation…”
BackgroundDoes β-amyloid plaque formation cause structural injury to neuronal processes?
Woodhouse, A., West, A. K., Chuckowree, J. A., Vickers, J. C., & Dickson, T. C. (2005) · Neurotoxicity Research · doi:10.1007/bf03033772 · Cited by 30
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“Fibrillar Ab appears to act as a nidus for the recruitment of astrocytes and activated microglial cells, which are often conspicuous around neuritic plaques (66, 152, 155), and for the deposition of other proteins, including a1-ACT, components of the complement cascade, apoE, apoJ, and AChE (1, 2, 66, 80, 110, 166, 16…”
Summers, K. L., Roseman, G. P., Schilling, K. M., Dolgova, N. V., Pushie, M. J., Sokaras, D., Kröll, T., Harris, H. H., Millhauser, G. L., Pickering, I. J., et al. (2022) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.2c01694 · Cited by 28
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“In AD, MAC is found together with plaques in both the brain parenchyma and blood vessels [26, 79].”
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Alzheimer’s disease: a review concerning immune response and microischemia
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“The creation of NFTs disrupts communication between neurons and impairs signal transmission [18,19].”
Taddei, R. N., Sanchez-Mico, M. V., Bonnar, O., Connors, T. R., Gaona, A., Denbow, D., Frosch, M. P., & Gómez‐Isla, T. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01370-3 · Cited by 23
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“Samples were analyzed in a single batch using a commercially available enzyme-linked immunosorbent assays (ELISA; Fujirebio, Ghent, Belgium) to measure CSF concentrations of Aβ42 (INNOTEST β-AMYLOID(1-42)), p-tau (INNOTEST PHOSPHO-TAU(181P)), and t-tau (INNOTEST hTAU).”
MethodAmyloid, memory and neurogenesis
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Novel ‘inflammatory plaque’ pathology in presenilin‐1 Alzheimer's disease
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“Moreover, with the exception of Ab-inducing mutations, none of these molecular and genetic factors appears to have absolute penetrance in causing the disorder: many individuals may possess several risk factors for AD, as well as express diffuse Ab and tau pathology, yet never develop the disorder [1].”
Elawad, M. A., Ayaz, M., Mosa, O. F., Usman, A., Hamdoon, A. A. E., Almawash, S., Salim, L. H. M., Ahmed, A., & Elkhalifa, M. E. M. (2024) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202400525 · Cited by 20
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“First, AD patients who also have short-term peripheral infections undergo a sudden decline in cognitive status [33]; second, plasma levels of alpha1-antichymotrypsin, interleukin-6, and C-reactive protein are increased before the clinical onset of various types of dementia, including AD [34]; third, the signs of infla…”
BackgroundPeripheral biomarkers of oxidative stress in aging and Alzheimer's disease
Marcourakis, T., Camarini, R., Kawamoto, E. M., Scorsi, L. R., & Scavone, C. (2008) · Dementia & Neuropsychologia · doi:10.1590/s1980-57642009dn20100002 · Cited by 21
“an inflammatory process.(25,26) Most of the neurodegenerative conditions are associated with a chronic inflammation.”
BackgroundKelliny, S., Zhou, X., & Bobrovskaya, L. (2025) · Journal of Neuroscience Research · doi:10.1002/jnr.70046 · Cited by 27
“But levels of soluble Aβ, the presence of CAA, NFT, and neuropil threads surrounding the amyloid core, besides inflammation, could only distinguish high pathology controls from AD patients (Lue et al. 1999, 1996).”
Drenthen, G. S., Elschot, E. P., van der Knaap, N., Uher, D., Voorter, P., Backes, W. H., Jansen, J. F. A., & van der Thiel, M. M. (2023) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.29056 · Cited by 20
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Should development of Alzheimer¿s disease-specific intravenous immunoglobulin be considered?
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“Central nervous system (CNS) inflammation may be a prerequisite for developing AD [87].”
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“Neuroinflammation has been wellrecognized in AD in which a prominent proinflammatory cytokine profile has been documented [13].”
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“Extensive evidence suggests that inflammation plays a major role in AD [48].”
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“Previous studies have consistently shown that individuals with AD pathology, but normal cognitive function, exhibit a density of dendritic spines similar to those without AD pathology, suggesting that resilient individuals experience minimal or no synapse loss (Lue et al., 1996; Boros et al., 2017).”
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“In humans, amyloid plaques have been found in brains of non-AD patients (Lue et al., 1996), indicating that to develop the AD characteristic symptoms due to potential Aβ proteotoxicity, more than just the formation of amyloid aggregates is required.”
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“The superior frontal gyrus was reported to have cortical synaptic loss and inflammation in AD patients [75].”
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“In the context of AD, overabundance of Aβ 42 has been reported to provoke inflammation in the brain including activation of microglia, a reaction implicated in the pathogenesis of AD (Lue et al., 1996; Hamelin et al., 2018).”
BackgroundCerebrospinal Fluid Inflammatory Markers in Alzheimer’s Disease: Influence of Comorbidities
Wang, Y., Emre, C., Gyllenhammar-Schill, H., Fjellman, K., Eyjolfsdottir, H., Eriksdotter, M., Schultzberg, M., & Hjorth, E. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666210330162207 · Cited by 8
Scintigraphic visualization of inflammation in neurodegenerative disorders
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Metadata
- Authors
- Lue, L.-F., Brachova, L., Civin, H. W., & Rogers, J.
- Affiliations
- Banner Sun Health Research Institute (US)
- Corresponding author
- Rogers, Joseph
- ORCID
- Lue, Lih-Fen
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1996-10
- Volume
- 55
- Issue
- 10
- Pages
- 1083-1088
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W4296391647
- Cited by
- 246
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 14 · 2020: 13 · 2019: 10 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 7
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, neuroinflammation, amyloid-beta deposition, neurofibrillary tangles, entorhinal cortex, superior frontal gyrus, synaptic loss, synaptophysin, microglial activation, MHC class II, neurodegeneration, non-demented elderly
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