Synaptic targeting by Aβ oligomers (ADDLS) as a basis for memory loss in early Alzheimer's disease

William L Klein*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

108 Scopus citations


Early diagnosis and treatment of Alzheimer's Disease (AD) ultimately will require identification of its pathogenic mechanism. Such a mechanism must explain the hallmark of early AD - A profound inability to form new memories. For many years, the most promising hypothesis maintained that memory failure derived from neuron death induced by insoluble deposits of amyloid fibrils. Newer findings, however, suggest that memory loss, especially in early AD, may be a failure in synaptic plasticity caused by small soluble Aβ oligomers ("ADDLs"). ADDLs are neurologically potent toxins that rapidly inhibit long-term potentiation and reversal of long-term depression, classic paradigms for learning and memory. In human samples, ADDLs show striking increases in AD brain and CSF. The ADDL hypothesis is considerably reinforced by nerve cell biology studies showing that ADDLs specifically attack synapses, essentially acting as gain-of-function pathogenic ligands. Selective damage by ADDLs to memory-linked synaptic mechanisms provides an appealing explanation for early AD memory loss and suggests that ADDLs provide a valid target for therapeutics and diagnostics.

Original languageEnglish (US)
Pages (from-to)43-55
Number of pages13
JournalAlzheimer's and Dementia
Issue number1
StatePublished - Jan 1 2006


  • Actin
  • Arc
  • Diagnostics
  • Glutamate receptors
  • Plasticity
  • ROS
  • Spines
  • Tau phosphorylation
  • Therapeutics

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience


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