The risk of Alzheimer's disease is determined, in part, by inheritance of specific alleles of ApoE. Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease. Synthetic peptides representing each of the four microtubule-binding domains of tau more avidly bind ApoE3 than ApoE4. Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. Understanding the molecular mechanisms of the high avidity, isoform-specific interactions of ApoE with tau may help in developing approaches for disease intervention.