The DOI matches its Crossref record; 47 of the 49 references it cites were found in a registry or an index.
A plasticity-based theory of the pathogenesis of Alzheimer's disease.
Abstract
Amyloid plaques (APs) and neurofibrillary tangles (NFTs) are the two diagnostic markers of Alzheimer's disease (AD). The neuropsychological features of AD are closely correlated with the distribution of the NFTs and therefore favor a disease process revolving around neurofibrillary degeneration. The genetics, however, favor a disease process revolving around the APs, principally because mutations in the amyloid precursor protein (A beta PP) are sufficient to cause AD. The inability to reconcile these two aspects of AD has prevented the formulation of a unified theory of pathogenesis. It is interesting to note that all genetic causes and risk factors of AD can increase the physiological burden of neuroplasticity. My hypothesis is that the resultant intensification of the plasticity burden leads to an initially adaptive upregulation of tau phosphorylation and A beta PP turnover, to the subsequent formation of NFTs and APs as independent consequences of excessive plasticity-related cellular activity, and to the eventual loss of neurons, dendrites, and synapses as the ultimate expression of plasticity failure. The two pathological markers of AD are therefore independent manifestations of a more fundamental process through which the many different genotypes of AD trigger an identical clinical and neuropathological phenotype.
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“This pattern is consistent with the hypothesis that AD pathology spreads centrifugally from limbic/paralimbic to higher-order association cortices (Mesulam, 2000).”
From Dynamics of Gray Matter Loss in Alzheimer's Disease (2003) · cites this paper as Mesulam, 2000
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Cites
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The Brain's Default Network: Anatomy, Function, and Relevance to Disease
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Metadata
- Authors
- MESULAM, M. ‐.
- Affiliations
- Northwestern University (US)
- Corresponding author
- MESULAM, M.‐MARSEL
- ORCID
- MESULAM, M.‐MARSEL
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2000-12
- Volume
- 924
- Issue
- 1
- Pages
- 42-52
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W2061837100
- Cited by
- 130
- References
- 49
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 7 · 2021: 6 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 10
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns020285-15)
- National Institute on Aging (AG13854, P30AG013854)
- National Institute of Neurological Disorders and Stroke (NS 20285)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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 pathogenesis, neuroplasticity, amyloid plaques, neurofibrillary tangles, tau phosphorylation, amyloid precursor protein, synaptic loss, neurodegeneration, genotype-phenotype correlation
- MeSH terms
- Alzheimer Disease, Brain, Humans, Neuronal Plasticity
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