The microtubule associated protein tau is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in neurons undergoing neurodegeneration in the brains of patients with Alzheimer disease (AD) . We investigated the isoform specific interaction of normal tau with the AD hyperphosphorylated tau (AD P-tau). We found that the binding of AD Ptau to normal human recombinant tau was t4L > t4S > t4 >; t3L, > t3S > t3 and that its binding to t4L was greater than to t3L. AD Ptau also inhibited the assembly of microtubules promoted by each tau isoform, and caused disassembly when added to preassembled microtubules. This inhibition and depolymerization of microtubules by the AD Ptau corresponded directly to the degree of its interaction with the different tau isoforms. In vitro hyperphosphorylation of recombinant tau (P-tau) conferred AD P-tau-like characteristics. Like AD P-tau, P-tau interacted with and sequestered normal tau and inhibited microtubule assembly. These studies suggest that the AD Ptau interacts preferentially with the tau isoforms that have the amino terminal inserts and four microtubule binding domain repeats and that hyperphosphorylation of tau appears to be sufficient to acquire AD P-tau characteristics. Thus, lack of amino terminal inserts and extra microtubule binding domain repeat in fetal human brain might be protective from Alzheimer neurofibrillary degeneration.