Pathological Substrates of Cognitive Decline in Alzheimer’s Disease
Abstract
The progressive development of Alzheimer's disease (AD)-related lesions such as neurofibrillary tangles,amyloid deposits and synaptic loss within the cerebral cortex is a main event of brain aging.Recent neuropathologic studies strongly suggested that the clinical diagnosis of dementia depends more on the severity and topography of pathologic changes than on the presence of a qualitative marker. However, several methodological problems such as selection biases, case-control design,density-based measures, and masking effects of concomitant pathologies should be taken into account when interpreting these data. In last years, the use of stereologic counting permitted to define reliably the cognitive impact of AD lesions in the human brain. Unlike fibrillar amyloid deposits that are poorly or not related to the dementia severity, the use of this method documented that total neurofibrillary tangles and neuron numbers in the CA1 field are the best correlates of cognitive deterioration in brain aging. Loss of dendritic spines in neocortical but not hippocampal areas has a modest but independent contribution to dementia. In contrast, the importance of early dendritic and axonal tau-related pathologic changes such as neuropil threads remains doubtful. Despite these progresses, neuronal pathology and synaptic loss in cases with pure AD pathology cannot explain more than 50% of clinical severity. The present review discusses the complex structure/function relationships in brain aging and AD within the theoretical framework of the functional neuropathology of brain aging.
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Numerous studies have documented a strong link between neocortical NFTs and cognitive loss.
“On the other hand, numerous studies have documented a strong link between neocortical NFTs and cognitive loss[26, 46, 48, 97, 123, 160, 169].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [46]
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · see citing works
Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease
Giannakopoulos, P., Herrmann, F. R., Bussière, T., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Gold, G., & Hof, P. R. (2003) · Neurology · doi:10.1212/01.wnl.0000063311.58879.01 · Cited by 1,118 · see citing works
Self-citationHippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment
Scheff, S. W., Price, D. A., Schmitt, F. A., & Mufson, E. J. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.012 · Cited by 1,017 · see citing works
Braak, F., Braak, H., & Mandelkow, E. (1994) · Acta Neuropathologica · doi:10.1007/bf00293315 · Cited by 769 · see citing works
Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease
Masliah, E., Mallory, M., Alford, M., DeTeresa, R., Hansen, L. A., McKeel, D. W., & Morris, J. C. (2001) · Neurology · doi:10.1212/wnl.56.1.127 · Cited by 720 · see citing works
Berg, L., McKeel, D. W., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., Baty, J., Coats, M., Norton, J., Goate, A. M., et al. (1998) · Archives of Neurology · doi:10.1001/archneur.55.3.326 · Cited by 657 · see citing works
Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines
Allen, P. B., Ouimet, C. C., & Greengard, P. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.18.9956 · Cited by 454 · see citing works
Quantitative synaptic alterations in the human neocortex during normal aging
Masliah, E., Mallory, M. E., Hansen, L. A., DeTeresa, R. M., & Terry, R. D. (1993) · Neurology · doi:10.1212/wnl.43.1_part_1.192 · Cited by 408 · see citing works
Sequence of Aβ-protein deposition in the human medial temporal lobe
Thal, D. R., Rüb, U., Schultz, C., Sassin, I., Ghebremedhin, E., Del Tredici, K., Braak, E., & Braak, H. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.8.733 · Cited by 370 · see citing works
Hof, P. R., Morrison, J. H., & Cox, K. (1990) · Journal of Comparative Neurology · doi:10.1002/cne.903010105 · Cited by 365 · see citing works
Self-citationNeuritic pathology and dementia in alzheimer's disease
McKee, A. C., Kosik, K. S., & Kowall, N. W. (1991) · Annals of Neurology · doi:10.1002/ana.410300206 · Cited by 358 · see citing works
Riley, K. P., Snowdon, D. A., Desrosiers, M. F., & Markesbery, W. R. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.06.019 · Cited by 303 · see citing works
Mitchell, T. W., Mufson, E. J., Schneider, J. A., Cochran, E. J., Nissanov, J., Han, L., Bienias, J. L., Lee, V. M. ‐., Trojanowski, J. Q., Bennett, D. A., et al. (2002) · Annals of Neurology · doi:10.1002/ana.10086 · Cited by 249 · see citing works
Memory and mental status correlates of modified Braak staging
Grober, E. H., Dickson, D. W., Sliwinski, M. J., Herman Buschke, L., Katz, M., Crystal, H., & Lipton, R. B. (1999) · Neurobiology of Aging · doi:10.1016/s0197-4580(99)00063-9 · Cited by 235 · see citing works
A critical discussion of the role of neuroimaging in mild cognitive impairment*
Wolf, H., Jelić, V., Gertz, H., Nordberg, A. K., Julin, P., & Wahlund, L. (2003) · Acta Neurologica Scandinavica · doi:10.1034/j.1600-0404.107.s179.10.x · Cited by 211 · see citing works
Hao, J., Janssen, W., Tang, Y., Roberts, J. A., McKay, H. M., Lasley, B., Allen, P., Greengard, P., Rapp, P., Kordower, J., et al. (2003) · The Journal of comparative neurology · doi:10.1002/cne.10837 · Cited by 202 · see citing works
Self-citationEvolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert
Sassin, I., Schultz, C., Thal, D. R., Rüb, U., Arai, K., Braak, E., & Braak, H. (2000) · Acta Neuropathologica · doi:10.1007/s004019900178 · Cited by 193 · see citing works
Kril, J., Patel, S., Harding, A., & Halliday, G. (2002) · Acta Neuropathologica · doi:10.1007/s00401-001-0477-5 · Cited by 190 · see citing works
Dickson, D. W. (1997) · Neurobiology of Aging · doi:10.1016/s0197-4580(97)00065-1 · Cited by 168 · see citing works
Bancher, C., Jellinger, K., Lassmann, H., Fischer, P., & Leblhuber, F. (1996) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/bf02189115 · Cited by 130 · see citing works
Cognitive impact of neuronal pathology in the entorhinal cortex and CA1 field in Alzheimer's disease
GUNTEN, A., KOVARI, E., BUSSIERE, T., RIVARA, C., GOLD, G., BOURAS, C., HOF, P., & GIANNAKOPOULOS, P. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.02.008 · Cited by 101 · see citing works
Stereologic Analysis of Microvascular Morphology in the Elderly
Bouras, C., Kövari, E., Herrmann, F. R., Rivara, C., Bailey, T. L., von Gunten, A., Hof, P. R., & Giannakopoulos, P. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000203077.53080.2c · Cited by 85 · see citing works
Self-citationAkram, A., Christoffel, D. J., Rocher, A. B., Bouras, C., Kövari, E., Perl, D. P., Morrison, J. H., Herrmann, F. R., Haroutunian, V. H., Giannakopoulos, P., et al. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.03.007 · Cited by 84 · see citing works
Self-citationNovel Method to Quantify Neuropil Threads in Brains from Elders With or Without Cognitive Impairment
Mitchell, T. W., Nissanov, J., Han, L.-Y., Mufson, E. J., Schneider, J. A., Cochran, E. J., Bennett, D. A., Lee, V. M.-Y., Trojanowski, J. Q., & Arnold, S. E. (2000) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540004801206 · Cited by 78 · see citing works
Clinical Validity of Aß-Protein Deposition Staging in Brain Aging and Alzheimer Disease
Gold, G., Kövari, E., Corte, G., Herrmann, F. R., Canuto, A., Bussière, T., Hof, P. R., Bouras, C., & Giannakopoulos, P. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.946 · Cited by 67 · see citing works
Self-citationTogo, T., Akiyama, H., Iseki, E., Uchikado, H., Kondo, H., Ikeda, K., Tsuchiya, K., de Silva, R., Lees, A., & Kosaka, K. (2004) · Acta Neuropathologica · doi:10.1007/s00401-004-0842-2 · Cited by 38 · see citing works
Dendritic spines: elementary structural units of neuronal plasticity
Segal, M. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)38070-1 · Cited by 32 · see citing works
Giannakopoulos, P., von Gunten, A., Kövari, E., Gold, G., Herrmann, F. R., Hof, P. R., & Bouras, C. (2007) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2007.00827.x · Cited by 31 · see citing works
Self-citationMorphometric image analysis of neuropil threads in Alzheimer's disease.
Markesbery, W., Wang, H. Z., Kowall, N., Kosik, K., & Mckee, A. (1993) · Neurobiology of Aging · doi:10.1016/0197-4580(93)90115-r · Cited by 16 · see citing works
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Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · see citing works
Self-citationAlzheimer's disease: experimental models and reality
Drummond, E., & Wisniewski, T. (2017) · Acta Neuropathologica · doi:10.1007/s00401-016-1662-x · Cited by 810 · see citing works
Webster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A., & Van Eldik, L. J. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00088 · Cited by 755 · see citing works
“…et al., 2002; Guillozet et al., 2003; Bennett et al., 2004; Kraybill et al., 2005; Holtzer et al., 2006; Markesbery et al., 2006; Koepsell et al., 2008; Whitwell et al., 2008; Beach et al., 2009; Brayne et al., 2009; Giannakopoulos et al., 2009; Sabbagh et al., 2010; Robinson et al., 2011).”
BackgroundNakajima, A., Aoyama, Y., Nguyen, T.-T. L., Shin, E.-J., Kim, H.-C., Yamada, S., Nakai, T., Nagai, T., Yokosuka, A., Mimaki, Y., et al. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.05.025 · Cited by 115 · see citing works
Mild Cognitive Impairment: Differential Atrophy in the Hippocampal Subfields
Hanseeuw, B. J., Van Leemput, K., Kavec, M., Grandin, C., Seron, X., & Ivanoiu, A. (2011) · American Journal of Neuroradiology · doi:10.3174/ajnr.a2589 · Cited by 110 · see citing works
ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status
Vasquez, J. B., Fardo, D. W., & Estus, S. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.09.058 · Cited by 101 · see citing works
Early secure attachment as a protective factor against later cognitive decline and dementia
Walsh, E., Blake, Y., Donati, A., Stoop, R., & von Gunten, A. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00161 · Cited by 84 · see citing works
Crowe, S. E., & Ellis‐Davies, G. C. R. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23306 · Cited by 15 · see citing works
Konsolaki, E., & Skaliora, I. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhu019 · Cited by 9 · see citing works
- Authors
- Giannakopoulos, P., Kövari, E., Gold, G., von Gunten, A., Hof, P. R., & Bouras, C.
- Affiliations
- University of Geneva (CH)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Hof, Patrick R.
- Venue
- Frontiers of Neurology and Neuroscience
- Publisher
- KARGER
- Published
- 2009
- Volume
- 24
- Pages
- 20-29
- ISSN
- 0300-5186 (ISSN-L)
- 1660-4431
- OpenAlex
- W1501924745
- Cited by
- 101
- References
- 30
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 8 · 2013: 15 · 2012: 11
- FWCI
- 33.78
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Monographs in clinical neuroscience/Frontiers of neurology and neuroscience/Monographs in neural sciences (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG-02219, AG 05138, P50AG005138, P01AG002219)
- 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, cognitive decline, neurofibrillary tangles, amyloid deposits, synaptic loss, dendritic spines, CA1 neurons, neuropil threads, dementia severity, brain aging, neuronal loss
- MeSH terms
- Alzheimer Disease, Brain, Cognition Disorders, Humans, Nerve Degeneration, Neurofibrillary Tangles, Disease Progression, Neuropil Threads, Plaque, Amyloid
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