Neuropathologic substrate of mild cognitive impairment

William R. Markesbery, Frederick A. Schmitt, Richard J. Kryscio, Daron G. Davis, Charles D. Smith, David R. Wekstein

Research output: Contribution to journalArticlepeer-review

402 Scopus citations


Objective: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). Methods: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs) in 4 neocortical regions and 4 ventromedial temporal lobe regions were counted in 10 patients with amnestic MCI and compared with the mean numbers in 23 normal control subjects and 10 patients with EAD, and then were compared with memory performance. All of the controls and patients were followed longitudinally. Results: Patients with MCI showed no significant difference (P>.05) in the number of diffuse plaques from that in normal controls or patients with EAD. In patients with MCI, the number of NPs was significantly elevated in all 4 neocortical regions and amygdala compared with controls (P<.01 to <.001). There were no significant differences (P>.05) in the number of NPs between MCI and EAD cerebral cortex, but significant increases were present for NPs in EAD amygdala and subiculum compared with MCI (P<.01). In patients with MCI compared with controls, the only significant increase in NFTs in the neocortex was in the parietal lobe. However, the number of NFTs was significantly elevated in MCI in all 4 ventromedial temporal lobe structures compared with controls (P<.01 to <.001). In comparing MCI with EAD, there were significant increases in NFTs in EAD in frontal and temporal lobes, amygdala, and subiculum (P<.01). The numbers of NPs and NFTs were significantly elevated in all of the neocortical regions and ventromedial temporal lobe regions in patients with EAD compared with controls (P<.001). Memory function was significantly correlated with NFTs in CA1 of the hippocampus (P<.01) and the entorhinal cortex (P<.05). Conclusions: In patients with amnestic MCI who were followed longitudinally, the early changes of Alzheimer disease were present. The NFTs were slightly more prominent than β-amyloid peptide deposition in the progression from normal to MCI to EAD. Ventromedial temporal lobe NFTs probably represent the substrate for memory decline in MCI. From a neuropathologic perspective, it appears that amnestic MCI is, in reality, EAD.

Original languageEnglish
Pages (from-to)38-46
Number of pages9
JournalArchives of Neurology
Issue number1
StatePublished - Jan 2006

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology


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