The degree to which neurofibrillary tangles (NFT), the hallmark lesions of Alzheimer disease (AD), contribute to the development of the cognitive symptoms of AD has been debated. NFTs are comprised of abnormally phosphorylated and conformationally altered tau proteins. Conformational changes in tau have been proposed to be among the earliest neurobiological changes in AD. This study examined whether conformational changes detected by antibodies MC1 and TG3 represent early abnormalities in the disease process by assessing their presence at different stages of dementia in multiple brain regions. Postmortem specimens from several neocortical regions were examined for conformational changes in tau by ELISA in subjects [n=81] who died at different stages of cognitive impairment. Concentrations of conformationally altered tau increased with increasing dementia severity and the levels of MC1 immunoreactivity increased in the frontal cortex of mildly demented subjects before the appearance of NFT bearing neurons, suggesting that conformational alterations in tau occur early in the course of AD and its cognitive symptoms and may precede histologically identified NFTs.