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Epilepsy and Cognitive Impairments in Alzheimer Disease
Open accessAbstract
Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.
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“Patients with EOFAD have an 87-fold increased incidence of seizures relative to the age-matched population compared to a threefold increase in seizure incidence in LOAD individuals [6].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [6]
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“Hyperexcitability is present in AD brain [142] and epilepsy was shown to promote plaque pathology [110].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [142]
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Metadata
- Authors
- Palop, J. J.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Palop, Jorge J.
- ORCID
- Palop, Jorge J.
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2009-04-01
- Volume
- 66
- Issue
- 4
- Pages
- 435
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC2812914
- OpenAlex
- W2098676436
- Cited by
- 684
- References
- 47
- Citations by year
- 2026: 16 · 2025: 31 · 2024: 47 · 2023: 50 · 2022: 38 · 2021: 46 · 2020: 34 · 2019: 47 · 2018: 33 · 2017: 40 · 2016: 47 · 2015: 42 · 2014: 43 · 2013: 41 · 2012: 39
- FWCI
- 28.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG023501, P50AG023501)
- National Institute of Neurological Disorders and Stroke (R01NS041787, NS041787)
- 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
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Keywords
- Alzheimer's disease, epilepsy, cognitive impairment, amyloid-beta, epileptiform activity, presenilin mutations, amyloid precursor protein, APOE ε4, early-onset Alzheimer's disease, transgenic mouse model, antiepileptic drugs
- MeSH terms
- Alzheimer Disease, Amnesia, Animals, Brain, Cognition Disorders, Disease Models, Animal, Electroencephalography, Epilepsy, Genetic Carrier Screening, Hippocampus, Humans, Mice, Transgenic, Nerve Net, Neural Inhibition, Synaptic Transmission, Picrotoxin, Amyloid beta-Peptides, tau Proteins, GABA Antagonists, Dentate Gyrus, Mice, Apolipoprotein E4
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