Cited by 130Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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A plasticity-based theory of the pathogenesis of Alzheimer's disease.

MESULAM, M.‐MARSEL·2000·Annals of the New York Academy of Sciences

DOI 10.1111/j.1749-6632.2000.tb05559.x

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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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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
DOI: 10.1111/j.1749-6632.2000.tb05559.x
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
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1881 d)
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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A plasticity-based theory of the pathogenesis of Alzheimer's disease.

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