Neurofibrillary changes of abnormally hyperphosphorylated tau are the key lesion in Alzheimer’s disease (AD) and a number of other tauopathies. Recent developments in the field of autosomal dominantly inherited dementias, in particular the frontotemporal dementias and Parkinsonism linked to chromosome 17 (FTDP-17) group, have shown that abnormalities in the tau gene result in neurofibrillary degeneration and cell death. Clinically this disorder presents with behavioral abnormalities, which are followed by dementia and, depending on the affected areas, by motor dysfunction. The location of the lesions does not seem to depend so much on the type of mutation as on the individual’s genetic background and may vary even in the same family with the identical mutation. For instance, in one family with a P 301 S mutation in exon 10 of tau, the father presented with frontotemporal dementia, whereas the son had corticobasal degeneration. 1 FTDP-17 is associated with both exonic and intronic mutations of the tau gene. The microtubule-associated protein (MAP) tau is a family of six proteins derived by alternative mRNA splicing 2,3 from a single gene located on chromosome 17. These molecular isoforms of tau differ in whether they contain three or four tubulin binding domains/repeats of 31 or 32 amino acids each near the C-terminal end and no, one, or two inserts of 29 amino acids each at the N-terminal end of the molecule. There are nine missense mutations on tau exons 9 to 13; all but three are on exon 10. 4-7 Exon 10 codes for the additional insert of the three 4-repeat tau isoforms. The resulting mutated taus possess an altered conformation 8 and a somewhat reduced ability to bind to and assemble microtubules. 9,10 In addition to the exonic mutations, mutations at several sites have been found in the predicted stem loop structure in the 5′ splice site to exon 10. These intronic mutations and certain mutations in exon 10 that are close to the stem loop, and thus able to disrupt it, lead to two- to sixfold higher proportion of tau mRNA containing exon 10 than in control brains. 5 The tau protein resulting from intronic mutations is normal, but the ratio of 4-repeat to 3-repeat isoforms is increased. Presently it is believed that due to the increased proportion of 4-repeat tau in the case of intronic mutations and the compromised biological activity of the tau with missense mutations, excess tau is not bound to the microtubules, which can then be hyperphosphorylated and would lead to neurofibrillary degeneration. In contrast to the FTDP-17 group of diseases, no mutations in the tau gene have been reported in AD at the time of writing this Commentary. In more than 90% of the AD patients the disease occurs sporadically above 60 years of age. In less than 5% of the cases the disease segregates with mutations in the amyloid precursor protein (APP), presenilin-1 (PS-1), or presenilin-2 (PS-2) genes. 11 Frameshift mutations of APP and ubiquitin at the level of transcription have been reported to be associated with sporadic and familial AD and Down’s syndrome. 12 The occurrence of the apolipoprotein E4 allele 13 and, most recently, mutations in the β2 macroglobulin gene 14 have been reported to be risk factors for the development of the late onset, sporadic AD. AD has two prominent neuropathological lesions, the extracellular deposits of the amyloid β peptide (Aβ) as plaques and the intraneuronal paired helical filaments (PHF) of abnormally hyperphosphorylated tau, which accumulate in the neuronal cell body as neurofibrillary tangles, in the neuropil (the so-called neuropil threads), 15 and in the dystrophic neurites surrounding the neuritic plaques. The direct relationship, if any, between the tangles and β-amyloid is not yet understood. At the one extreme, in the normal aged brain there is the significant β-amyloid accumulation and minimal neurofibrillary degeneration, whereas in the early onset familial AD with mutations in the β-APP or presenilin gene, massive β-amyloid deposits, tau hyperphosphorylation, and tangle formation are always seen. The other extreme situation is represented by extensive neurofibrillary degeneration and minimal β-amyloidosis. These include tauopathies like the tangle-predominant form of senile dementia (tangle-only dementia), Guam Parkinsonism dementia complex, dementia with argyrophilic grains, Nieman Pick’s disease type C, subacute sclerosing panencephalitis, Pick’s disease, and the dementia group with mutations in the tau gene. 16 Although at present the exact role of PHF and β-amyloid in the pathogenesis of AD is not established, there is growing evidence from a number of laboratories that the intellectual deterioration in AD patients is associated with neurofibrillary degeneration. 17-20 A third and well characterized phenomenon is synaptic loss and cell death exceeding 50% in certain areas of the brain. 21,22