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Marwan N. Sabbagh, MD; Flora Shah, BS; Richard T. Reid, PhD; Lucia Sue, BA; Donald J. Connor, PhD; Lars Kristofer N. Peterson, BS; Thomas G. Beach, MD, PhD

Arch Neurol. 2006;63:1771-1776.

Background  Neurochemical and pathologic studies show that mild cognitive impairment (MCI) is frequently a transitional state between normal aging and Alzheimer disease (AD). Neuropathologic sample sizes have been limited because relatively few individuals with MCI die before dementia develops. Decreased neocortical nicotinic receptor binding is characteristic of AD but has not been investigated in subjects with MCI.

Objective  To assess nicotinic receptor binding and pathologic differences in control subjects with no dementia (ND) and in subjects with clinically and pathologically described MCI or Alzheimer disease.

Design  This was a clinicopathologic analysis. Subjects with ND had no demonstrable cognitive or functional impairment. Subjects with MCI met Petersen clinical criteria for single- or multiple-domain amnestic MCI and died before the disorder progressed to AD. Subjects with AD met National Institute for Neurological Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association clinical criteria for AD. All subjects underwent a complete diagnostic and semiquantitative neuropathologic examination. Data were examined after both clinical and histopathologic classification of subjects.

Setting  Sun Health Research Institute Brain Donation Program, and Arizona Alzheimer Disease Center.

Participants  Twenty-one control subjects with ND, 8 subjects with MCI, and 70 subjects with AD, prospectively followed up to autopsy.

Main Outcome Measures  Nicotinic acetylcholine receptor binding value, total tangle density, total plaque density, and Braak stage.

Results  At the last examination before death, subjects with AD were significantly younger, less educated, and more cognitively and globally impaired compared with subjects with ND. When categorized by clinical diagnosis, MCI was always intermediate between ND and AD. On the whole, MCI was pathologically intermediate between ND and AD for senile plaque density, neurofibrillary tangle density, and Braak stage, but some subjects with MCI lacked neuritic plaques entirely. Binding for nicotinic acetylcholine receptors did not differ between the ND and MCI groups, but it was significantly less in the AD group.

Conclusions  Most MCI may be considered a transitional state between ND and AD clinically and neuropathologically, but in some MCI cases there is lack of neuritic plaques, and, therefore, it cannot be considered early AD. Nicotinic receptor binding seems to be lost during the transition from MCI to AD.

Author Affiliations: Cleo Roberts Center for Clinical Research (Drs Sabbagh and Connor, Ms Shah, and Mr Peterson) and W. H. Civin Laboratory for Neuropathology (Ms Sue and Dr Beach), Sun Health Research Institute, Sun City, Ariz; and the Erik and Ese Banck Clinical Research Center, La Jolla, Calif (Dr Reid).

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