DNA damage, as demonstrated by in situ Tdt-mediated dUTP-X-nick end labeling (TUNEL), is widespread in the cerebral cortex in end-stage Alzheimer disease, but has not been previously correlated with stages of neurofibrillary tangle formation. To assess possible relationships between neurofibrillary tangle formation and DNA damage, we used tau immunohistochemistry and TUNEL in tangle-rich fields of tissue sections of subiculum and parahippocampal cortex tissue from 12 Alzheimer and 6 control patients. Structure were classified and quantified as tau-/ TUNEL-, tau-/ TUNEL+, tau+/ TUNEL-, or tau+/ TUNEL. Tau+ structures were subclassified into 4 stages (0-3) based on neurofibrillary tangle morphology. The total number of TUNEL+ neurons was significantly less in control than in Alzheimer patients (35 ± 7.2 vs 90 ± 9.3/ mm2; mean ± SEM; p < 0.05). The number of tau+/ TUNEL+ neurons (40 ± 1/mm2) was less than that of tau-/ TUNEL- neurons (68 ± 7/mm2) or tau-/ TUNEL+ neurons in the same fields (50 ± 4/mm2, p < 0.0001). Tau+/ TUNEL- structures were fewer in number (21 ± 1/mm2), with a third of these representing acellular “ghost tangles” (stage 3). Tau+ neurons were more likely than tau- neurons to be TUNEL+ (64 ± 6% vs 44 ± 2%; mean ± SEM; p < 0.01), although most TUNEL+ neurons were tau-, even in these selected, tangle-rich fields. TUNEL positivity was not uniformly distributed among tangle stages. TUNEL positivity was less common among early (stage 0) tangles than in tau- neurons (21 ± 6% vs 44 ± 2%; p < 0.001), but this rose to 53% among intermediate (stage 1) tangles, and to 87% among late (stage 2) tangles. We suggest that early stages of neurofibrillary tangle formation occur in a subpopulation of relatively healthy (TUNEL-) neurons, and that tangle progression is accompanied by increasing neuronal morbidity.