Apolipoprotein (APO, gene; apo, protein) D, a member of the lipocalin family, has been implicated in several, pathological conditions but neither its physiologic function(s) nor ligand(s) has been clearly identified so far. Presuming a role in nerve de- and regeneration, several groups investigated apoD alterations in Alzheimer's disease (AD). Reported data, however, were not unanimous. We determined apoD protein levels in the hippocampus in a large, carefully matched autopsy case sample. ApoD levels were compared with the severity of neuropathological changes as determined by the Braak classification and with APOE genotype, a major risk factor for developing AD. ApoD was found to be related to the severity of AD-related neurofibrillary (NF) changes and not to old age alone. No correlation was found to amyloid deposits. Brain samples with widespread NF changes showed significantly higher apoD than cases with low Braak stages. This increase, however, was restricted to the APOE epsilon3/3 group, whereas the APOE epsilon4 group did not show significant variations in hippocampal apoD.