The total amount of hyperphosphorylated tau protein (p-tau load), present as neurofibrillary tangles (NFTs), neuropil threads or plaque neurites, was quantified in the frontal cortex of 109 cases of sporadic Alzheimer's disease (AD) and 35 cases of familial AD due to missense mutations in the presenilin-1, presenilin-2 and amyloid precursor protein genes. p-tau load was inversely correlated with age at onset of illness in both sporadic and familial AD but not with duration of disease. There was no difference in p-tau load between cases of familial AD and others with sporadic AD, matching the familial cases for apolipoprotein E (APO E) genotype. However, p-tau was greater in cases of familial and sporadic AD in the presence of APO E epsilon4 allele and increased with gene dose. Conversely, p-tau load tended to be lower when epsilon2 allele was present. In sporadic AD, tau load was highly significantly correlated with amyloid beta40 (Abeta40), but not Abeta42(43), load. These data indicate that the burden of pathological tau deposited in the brain in both familial and sporadic AD is favoured in the presence of APO E epsilon4 allele and also related to the amount of Abeta40, this also being higher when epsilon4 allele is present. Abeta40 plaques are rich in microglial cells and it is possible that p-tau pathology in AD is triggered by reaction of microglial cells to the presence of Abeta40 and not this peptide directly.