This isn't the first paper I've seen to argue the point that there should be a greater focus on tau aggregation in Alzheimer's disease, and that tau may be more important to the progression of the condition. As I'm sure the readers here are aware, Alzheimer's is characterized by the buildup of both amyloid-β and tau in the brain. Forms of these normally soluble proteins precipitate into solid deposits that are accompanied by a complex halo of biochemistry that degrades the function of neurons and ultimately kills these cells. The primary focus for development of therapies has long been the removal of amyloid-β, but despite enormous effort there is no light at the end of the tunnel yet. The history of clinical trials for amyloid-β clearance is one of unremitting failure, even recently in trials that produced evidence for amyloid-β to be removed to some degree in patients.
It is much debated as to whether trials are failing because amyloid-β is the wrong target, despite being harmful in and of itself, or because Alzheimer's is a hard problem. Alzheimer's research has proceeded in parallel with mapping the brain at the necessary level to talk about how exactly it is damaged by protein aggregates, and also in parallel with the development of immunotherapy technologies, both of which are challenging areas of research and development. The biochemistry of the brain, its operation, and its failure modes are all enormously complex. We seem to be reaching a tipping point, however, in which discontent with the focus on amyloid-β is spilling over into greater emphasis and funding for alternatives. Rightly or wrongly in this specific case, I think that diversity in approaches is almost always better in the long term.
The hallmarks of Alzheimer's disease (AD) pathology are marked by accumulation of extracellular amyloid-β (Aβ) plaques in the brain followed by intracellular neurofibrillary tangle (NFT) growth. Aβ upregulates the generation of NFTs by increasing glycogen synthase kinase-3 (GSK-3) activity, leading to the phosphorylation of tau. Phosphorylated tau (pTau) begins to self-assemble to form NFTs. Aβ plaques, soluble Aβ oligomers, and NFTs interfere with normal neuronal cell function by disrupting synaptic signaling. Each protein's accumulation leads to neuron damage, eliciting diminished brain mass and cognitive function.
The removal of Aβ plaques does not influence elimination of NFTs after NFTs have been established in the brain, but early intervention can prevent pTau development. Therefore, targeted late stage treatments may specifically eliminate Aβ without impacting pTau levels that have already accumulated, which enables NFTs to continue amplifying cognitive deficits. Comparison of differences in pTau and Aβ levels in treated mice illuminate differences between the proteins' impact on cognitive function. For example, pTau levels were reduced by chemical treatment as Aβ levels continued to increase, yet cognitive function improved. This result implies that there is a quantitative difference between how the two proteins effect cognitive deterioration, and moreover, that decreasing pTau may ultimately be more important than reducing Aβ in the quest to successfully treat AD.
The Amyloid Cascade Hypothesis states that Aβ is the center piece in AD pathology leading to hyperphosphorylation of tau and numerous neurotoxic pathways causing cell death. Treatments targeting Aβ and Aβ precursors have failed to pass clinical trials to improve patient outcomes. The presence of Aβ is associated with a decrease in cognitive performance; however, the quantitative level of Aβ inconsistently predicts the amount of cognitive decline. Instead, it is suggested that other contributors, such as the hyperphosphorylation of tau, are the functional cause of degeneration after the initial onset of AD.
The present study compares the effects of Aβ and pTau levels on cognitive performance in the Morris water maze (MWM) and Novel Object Recognition (NOR) through a large-scale meta-analysis of 3xTg-AD mouse model experiments. The triple-transgenic mouse model (3xTg-AD) of AD expresses tangle and plaque pathology as well as synaptic dysfunction. Multiple linear regression confirmed pTau is a stronger predictor of MWM performance than Aβ. Despite pTau's lower physical concentration than Aβ, pTau levels more directly and quantitatively correlate with 3xTg-AD cognitive decline.