This aim of the present study was to identify whether apoptotic features relate to the degree of cortical neuronal loss in cases with variable cortical degeneration. Neuronal apoptosis was assessed using histochemical and morphological criteria in cases with Alzheimer's disease (AD, n=7) or Lewy bodies (n= 11) compared with controls (n=11). AD cases had both significant plaque and tangle formation but no Lewy bodies, while cases with Lewy bodies had significant plaque formation but no tangles. Cortical sections were stained using (TdT)-mediated UTP nick end labelling (TUNEL), propidium iodide, and cell and pathology-specific labels. Cells identified as non-neuronal were excluded. Large cortical nuclei were classified as abnormal if they were TUNEL-positive with DNA condensation across the nucleus and no visible nucleolus, and further subdivided according to the presence or absence of visible neuronal cytoplasm. Nuclei were considered morphologically normal regardless of TUNEL staining if they possessed a clear nucleolus. Cortical fields containing the greatest density of TUNEL-positive nuclei were regionally sampled and the proportion of all classified nuclei calculated. Analysis of variance was used to identify any significant relationships. Only AD cases had significant numbers of abnormal nuclei (23+/-6%, P=0.002) and a corresponding decrease in normal neurons (28+/-7% loss, P= 0.004). Absolute neuronal density was also decreased in AD (AD density 64+/-11% of other cases, P=0.02). Abnormal nuclei were not associated with plaque or tangle pathology. Our results suggest that nuclear abnormalities appear restricted to AD cases with substantial tau deposition and are related to the degree of neuronal degeneration.