Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease.

In this report we quantitatively assess the numbers of intracellular and extracellular neurofibrillary tangles (NFT) in the brains of a series of individuals with Alzheimer's disease and of controls and correlate these with neuronal loss. Our data indicate that in some cases, NFT are not removed from the brain throughout the disease process. This finding, together with our previous demonstration of carbonyl-related modifications in NFT, provides additional evidence that the protein constituents of NFT are resistant to proteolytic removal, possibly as a result of extensive cross-links. Additionally, correlation between the number of NFT and neuronal loss indicates that there are at least two distinct mechanisms responsible for neuronal death in Alzheimer's disease that are directly and indirectly related to the presence of neurofibrillary pathology.