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Joseph L. Price, DPhil; Andy I. Ko, BA; Marcus J. Wade, BA; Sarah K. Tsou; Daniel W. McKeel, MD; John C. Morris, MD

Arch Neurol. 2001;58:1395-1402.

Objectives  To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration.

Methods  Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD—the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1.

Results  There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group.

Conclusions  There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.

From the Departments of Anatomy and Neurobiology (Dr Price, Messrs Ko and Wade, and Ms Tsou), Pathology and Immunology (Drs McKeel and Morris), and Neurology (Dr Morris) and the Alzheimer's Disease Research Center (Drs Price, McKeel, and Morris), Washington University School of Medicine, St Louis, Mo.

Corresponding author and reprints: Joseph L. Price, DPhil, Department of Anatomy and Neurobiology, Campus Box 8108, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110 (e-mail: PriceJ{at}Thalamus.wustl.edu).

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