Elevated levels of tau in cerebrospinal fluid: Implications for the antemortem diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a heterogeneous group of dementias characterized by progressive cognitive impairments as well as by the accumulation of abundant extracellular deposits of Aβ and intra-neuronal neurofibrillary lesions in selectively vulnerable regions of the AD brain. The latter abnormalities (e.g. neurofibrillary tangles, dystrophic neurites, neuropil threads) are aggregates of paired helical filaments (PHFs) formed from altered tau proteins (PHFtau). Although PHFtau and normal central nervous system (CNS) tau are phosphorylated at nearly the same sites, PHFtau is phosphorylated to a greater extent, and alterations in the activity of CNS kinases and phosphatases most likely contribute to the pathogenesis of PHFtau. Since the abundance of neurofibrillary lesions correlates with the dementia in AD, the generation of PHFtau and the formation of neurofibrillary lesions may be part of a cell death pathway leading to massive neuron loss and dementia in AD. Building upon these and other insights into altered tau metabolism in AD, a series of studies suggest that the diagnosis of AD may be supported in living patients by determining the concentration of tau in cerebrospinal fluid (CSF). We review these promising studies here, and discuss them in the context of current understanding of the pathobiology of AD.