Previous studies have shown that nerve cells containing NADPH-diaphorase (NADPH-d) are relatively resistant to various damaging processes. NADPH-d has been found to be colocalized with somatostatin (SOM) and neuropeptide Y (NPY) in neuronal populations of several forebrain regions. We have investigated the anatomical distribution, morphology and cell sizes of NADPH-d neurons in amygdala and temporal cortex in Alzheimer's disease (AD) compared to controls of different age. NADPH-d cells and fibers were present in layers II-VI of the cortex and in the white matter below the cortical mantle. In the amygdaloid complex, NADPH-d cells and processes were observed in almost all subnuclei. In the amygdala of aged controls, only insignificant atrophic alterations of NADPH-d neurons and fibers were seen. In AD, a moderate, but significant shift towards an increased number of medium-to small-sized neurons was measured in amygdala and cortex, indicating cell shrinkage during the course of the disease. However, there were no differences when comparing NADPH-d staining in amygdaloid subregions in AD cases that contained numerous neuritic plaques (i.e., accessory basal nucleus) with areas that were relatively free of lesions (i.e., lateral nucleus). Analysis of cell size of SOM- and NPY-immunoreactive cells revealed only slight atrophic changes during aging. In AD, however, a significant atrophy of somatostatin neurons in temporal cortex was found, whereas no further cell shrinkage was noted for NPY as compared to aged controls. Colocalization tests demonstrated a large overlap between NPY, SOM and NADPH-d in the amygdala, whereas a subpopulation of cortical SOM neurons, predominantly localized in upper layers, showed a lack of NADPH-d. Our findings of a relative stability of a selective subclass of neurons during aging and AD support the hypothesis that cellular pathology may affect only specific neuronal populations while others might be spared.