For the past 20 years, Alzheimer’s disease research and drug development have largely been dominated by the theory that the formation of β-amyloid plaques in the brain plays a central role in clinical dementia. However, research has consistently shown that β-amyloid plaques are poorly correlated with dementia, and results from clinical trials based on this approach have been disappointing.
According to the tau hypothesis, which the TauRx team has been focusing on for nearly three decades, abnormal aggregation of tau protein ultimately leads to the formation of tangles within nerve cells in the brain. Once initiated, the tau aggregation process continues of its own accord, consuming the normal form of tau protein in the process and spreading the aggregation cascade into previously healthy nerve cells.
In Alzheimer’s, tau tangles first destroy nerve cells critical for memory and then destroy neurons in other parts of the brain as the tau aggregation process spreads from neuron to neuron throughout the brain. Tau tangles first appear in the brain some 20 years before the clinical impact of the disease process becomes apparent.
Tau Protein Aggregation Leads to Neuronal Cell Dysfunction and Eventually Cell Death
More recently, the process whereby the tau aggregation cascade recruits normal tau and transmits the aggregation to other nerve cells in particular brain circuits was shown to be a paradigm for understanding a range of other neurodegenerative diseases. The pathological theme of self-replicating protein aggregation leading to neuronal destruction and debilitating diseases now provides a unifying explanation for Parkinson’s disease, Huntington’s disease, frontotemporal dementia, and of course Alzheimer’s disease. What differs between diseases is the aggregating protein species and the neuronal circuits involved.