Changes in the interaction between sex hormones and the cholinergic system are presumed to play a role in cognitive decline in aging and Alzheimer's disease (AD). The hippocampus is one of the most strongly affected brain structures in AD and the vertical limb of the diagonal band of Broca (VDB) is its major source of innervation. In the present study we found, surprisingly, for the first time that the neuronal metabolic activity as measured by the size of the Golgi apparatus in the VDB gradually increases after the age of 50 years in controls and that this process starts earlier and is more pronounced in Alzheimer's disease patients. Neuronal metabolic activity in the VDB was significantly higher in AD than in control patients younger than 70 years of age and was higher in control patients over 70 years than in control patients younger than 70 years of age. The activation of VDB neurons during aging was accompanied by an increased nuclear estrogen receptor (ER) beta staining, which was stronger in patients over 70 years of age than in younger subjects (in both controls and AD patients). Interestingly, as in the nucleus basalis of Meynert, nuclear ERalpha expression was markedly enhanced in AD patients compared to controls independent of age. In addition, evidence was found for the influence of APOE genotype on ERalpha and ERbeta staining in the human VDB in aging and in AD. APOE genotype was positively correlated (epsilon 2 < epsilon 3 < epsilon 4) with the percentage of cytoplasm ERalpha-positive VDB neurons in elderly control male and female subjects and with both nuclear and cytoplasm ERbeta-positive neurons in control women. In conclusion, the VDB is compensatory activated and shows more nuclear ER expression in aging and AD in a sex- and APOE genotype-dependent way. So neither global degeneration or a strongly decreased neuronal metabolism nor a lack of sex hormone receptors in the VDB seems to contribute to the decline in cognition in aging or AD in which the hippocampus plays such a crucial role.