The Significance of Tau Aggregates in the Human Brain.

Neurofibrillary degeneration has attracted the attention of neuroscientists as both a hallmark of the disease and a subject for experimentation for more than a century. Recent studies implicate phosphorylated tau (p-tau) directly in neurodegenerative disease pathogenesis, although the human data continue to raise questions. P-tau accumulates with age in a roughly hierarchical manner, but avoids abundance in the neocortex unless co-occurring with amyloid-β. Neurodegenerative tauopathies tend to have p-tau morphologies that differ from aging and Alzheimer's disease. Tau isoforms (3R vs. 4R) have a tendency to vary with tauopathy phenotype for unknown reasons. Selective vulnerability to p-tau and spatial-temporal disconnect from amyloid-β are evident in aging. P-tau assessment at autopsy involves tissue decomposition, which may skew microanatomical observations toward limited biological meaning. Two major consensus guidelines for interpreting p-tau at autopsy emphasize the challenges of clinicopathologic correlation, and reinforce the observation that regional neurodegeneration is a better correlate of clinical signs than is proteinopathy. Despite the proliferation of interesting and novel theories related to tau-mediated pathogenesis, the weight of the human observations suggests that neurofibrillary degeneration is an epiphenomenal hallmark of aging and disease rather than an epicenter of neurotoxicity. This is consistent with numerous tau-targeted therapeutic strategies that have been unsuccessful to date.