The distribution of acetylcholinesterase (AChE)-rich pyramidal neurons was studied in the cortices of 7 Alzheimer's Disease (AD) patients and 4 normal-aged subjects. Both groups showed a characteristic distribution of these neurons with the highest density in motor and premotor areas, moderate density in association cortices, and low density in limbic-paralimbic areas. Three areas (Brodmann areas 6,22, and 24) were chosen for quantitative analysis. The number of pyramidal neurons that display an AChE-rich staining pattern was significantly reduced in AD patients. Nerve cell density was not significantly different in adjacent Nissl-stained sections. The density of AChE-rich (cholinergic) fibers was also decreased in all three cortical areas of the AD patients but was not correlated with the number of AChE-rich neurons. Loss of AChE-rich neurons was more pronounced in areas with high counts of tangles. These findings show that layer 3 and 5 pyramidal neurons in AD display a reduction of AChE activity. This phenomenon can not be attributed to the well known loss of cortical neurons or cholinergic innervation in AD.