In the human brain, the distribution of perineuronal nets occurring as lattice-like neuronal coatings of extracellular matrix proteoglycans ensheathing several types of non-pyramidal neurons and subpopulations of pyramidal cells in the cerebral cortex is largely unknown. Since proteoglycans are presumably involved in the pathogenesis of Alzheimer's disease, we analysed the distribution pattern of extracellular chondroitin sulphate proteoglycans in cortical areas, including primary motor, primary auditory and several prefrontal and temporal association areas, in normal human brains and in those showing neuropathological criteria of Alzheimer's disease. In both groups, neurons with perineuronal nets were most numerous in the primary motor cortex (approximately 10% in Brodmann's area 4) and in the primary auditory cortex as a representative of the primary sensory areas. Their number was lower in secondary and higher order association areas. Net-associated pyramidal cells occurred predominantly in layers III and V in motor areas, as well as throughout lower parts of layer III in the primary auditory cortex and neocortical association areas. In the entorhinal cortex, net-associated pyramidal cells were extremely rare. In brains showing hallmarks of Alzheimer's disease, the characteristic patterns of hyperphosphorylated tau protein, stained with the AT8 antibody, largely excluded the zones abundant in perineuronal nets and neuropil-associated chondroitin sulphate proteoglycans. As shown in double-stained sections, pyramidal and non-pyramidal neurons ensheathed by perineuronal nets were virtually unaffected by the formation of neurofibrillary tangles even in severely damaged regions. The distribution patterns of amyloid B deposits overlapped but showed no congruence with that of the extracellular chondroitin sulphate proteoglycans. It can be concluded that low susceptibility of neurons and cortical areas to neurofibrillary changes corresponds with high proportions of aggregating chondroitin sulphate proteoglycans in the neuronal microenvironment.