Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer’s Disease

Rebecca P. Haberman, Audrey Branch, Michela Gallagher

Research output: Contribution to journalReview articlepeer-review

Abstract

Sporadic late-onset Alzheimer’s disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.

Original languageEnglish (US)
Pages (from-to)662-676
Number of pages15
JournalNeurotherapeutics
Volume14
Issue number3
DOIs
StatePublished - Jul 1 2017

Keywords

  • Amnestic mild cognitive impairment (aMCI)
  • Cognitive aging
  • Hippocampal CA3
  • Late-onset Alzheimer’s disease
  • Levetiracetam (Keppra)

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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