Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment

Stephen W. Scheff, Douglas A. Price, Frederick A. Schmitt, Elliott J. Mufson

Research output: Contribution to journalArticlepeer-review

772 Scopus citations


One of the major neuropathological findings in the brains of individuals with Alzheimer's disease (AD) is a loss of synaptic contacts in both the neocortex and hippocampus. Here we report, for the first time, an estimate of the total number of synapses in the outer molecular layer (OML) of the human dentate gyrus, in individuals with early Alzheimer's disease (eAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI). An unbiased stereologic sampling scheme coupled with transmission electron microscopy to directly visualize synaptic contacts, was used to estimate the total number of synapses in short postmortem autopsy tissue. Individuals with eAD had significantly fewer synapses than the other two diagnostic groups. Seventy-five percent of the individuals with MCI had synaptic values that were lower than the NCI group mean. The number of synapses showed a significant correlation with the subject's Mini-Mental State score and with cognitive tests involving delayed recall. Synaptic loss showed no relationship to Braak stage or to apoE genotype. The volume of the OML was significantly reduced in eAD compared to the other two diagnositic groups that were not different from each other. These data suggest that a loss of afferents from the entorhinal cortex underlie the synapse loss seen in eAD. This study supports the concept that synapse loss is an early event in the disease process and suggests that MCI may be a transition stage between eAD and NCI with synaptic loss a structural correlate involved in cognitive decline.

Original languageEnglish
Pages (from-to)1372-1384
Number of pages13
JournalNeurobiology of Aging
Issue number10
StatePublished - Oct 2006

Bibliographical note

Funding Information:
This work was supported by grants from the NIH (National Institute on Aging, AG14449, AG10161, AG10688 and AG19241. We are indebted to the altruism and support of the participants in the ROS. A list of participating groups can be found at the website: http://www.rush.edu/rumc/page-R12394.html . We thank Dr. D.A. Bennett, director of the ROS clinical core, Drs. E. Cochran and J.A. Schneider past and present director of the ROS neuropathology core, Joanne Wuu for statistical consultation and Dr. W.R. Markesbery, director of the UKADRC.


  • Aging
  • Cognition
  • Hippocampus
  • Limbic system
  • Memory
  • Synapse

ASJC Scopus subject areas

  • Neuroscience (all)
  • Aging
  • Developmental Biology
  • Clinical Neurology
  • Geriatrics and Gerontology


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