Epilepsy and cognitive impairments in Alzheimer disease

Arch Neurol. 2009 Apr;66(4):435-40. doi: 10.1001/archneurol.2009.15. Epub 2009 Feb 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Amnesia / drug therapy
  • Amnesia / genetics
  • Amnesia / physiopathology
  • Amyloid beta-Peptides / physiology
  • Animals
  • Apolipoprotein E4 / genetics
  • Brain / drug effects
  • Brain / physiopathology*
  • Cognition Disorders / drug therapy
  • Cognition Disorders / genetics
  • Cognition Disorders / physiopathology*
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology
  • Disease Models, Animal
  • Electroencephalography
  • Epilepsy / genetics
  • Epilepsy / physiopathology*
  • GABA Antagonists / therapeutic use
  • Genetic Carrier Screening
  • Hippocampus / physiopathology
  • Humans
  • Mice
  • Mice, Transgenic
  • Nerve Net / physiopathology
  • Neural Inhibition / genetics
  • Neural Inhibition / physiology
  • Picrotoxin / therapeutic use
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • GABA Antagonists
  • tau Proteins
  • Picrotoxin