A unifying hypothesis for Alzheimer's disease: from plaques to neurodegeneration

Abstract

Evidence suggests that amyloid β is highly toxic to synapses in a phospho-Tau-dependent manner. Here, I present a hypothesis that links previous evidence from the first rise of amyloid β through to Tau tangles and neurodegeneration. In the immediate vicinity of plaques, concentrated soluble amyloid β occurs in equilibrium with deposited forms. Initially, plaques cover only a small percentage of brain volume. Microglia, by efficiently removing damaged synapses, may prevent spread of damage along the axon, restricting damage to the immediate vicinity of plaques. However, as plaque load increases, as seen in Alzheimer's disease, an individual axon may suffer multiple points of damage, leading to dissociation of Tau, formation of a tangle, and loss of the axon. As more axons suffer this fate, the network eventually degenerates. According to this hypothesis, the degree of plaque load that an individual can tolerate would depend on the efficiency of their microglia in removing amyloid-β-damaged synapses and the distribution of plaques, relative to axon trajectories, would determine the eventual cognitive symptoms.