AUTOSOMAL-DOMINANT DEMENTIA WITH WIDESPREAD NEUROFIBRILLARY TANGLES

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by ea rly-onset dementia with long disease duration, with an autosomal domin ant inheritance pattern, and with I-rich neurofibrillary pathology fou nd in the brain post mortem. The average age at presentation was 55 ye ars with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologi c examination demonstrated abundant intraneuronal neurofibrillary tang les (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, s ubstantia nigra, pens, and medulla. Only sparse neocortical tangles we re present and amyloid plaques were absent. The tangles were recognize d by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF -1, 12E8, ATG, AT18, AT30) in tau proteins. Electron microscopy of NFT s in the dentate gyrus and midbrain demonstrated paired helical filame nts. Although the clinical phenotype resembles Alzheimer's disease, an d the neuropathologic phenotype resembles progressive supranuclear pal sy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.