The Framework for an Integrative Theory of Alzheimer's Disease.

The manuscript describes how the framework of the integrative hypothesis of Alzheimer's disease (AD) can be deciphered using existing experimental and clinical data. First, the analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies indicate a correlation between AD diagnosis and heightened cellular uptake of beta-amyloid. Since beta-amyloid must be taken up by cells to become toxic, its uptake rate correlates with neurodegeneration. Also, aggregation seeds cannot form extracellularly due to low beta-amyloid levels in interstitial fluid but can develop inside lysosomes. Consequently, the density of extracellular aggregates correlates positively with cellular amyloid uptake rate. The model, which ties both beta-amyloid cytotoxicity and aggregation to cellular uptake, accurately predicts AD diagnosis patterns in the population. Second, beta-amyloid enters cells through endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage and explains intracellular ion disturbances (including calcium overload) after exposure to extracellular beta-amyloid. The permeabilization is caused by channels formed in lysosomal membranes by some amyloid fragments produced by proteolysis of full-length beta-amyloid. Some membrane channels are large enough to leak cathepsins to the cytoplasm, causing necrosis or apoptosis. Also, local spikes of calcium cytosolic concentration due to calcium leakage from lysosomes can activate calpains, contributing to cell death. In surviving cells, accumulation of damaged lysosomes results in autophagy failure and slow mitochondrial recycling, promoting the production of reactive oxygen species and further cell damage. In this framework, AD's etiology is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization and the appearance of activated proteases in the cytoplasm. The correlation between AD diagnosis and the density of amyloid aggregates occurs because both amyloid cytotoxicity and extracellular aggregate formation stem from cellular amyloid uptake. To reflect key processes, we call this framework the Amyloid Degradation Toxicity Hypothesis of Alzheimer's Disease. It explains various phenomena and paradoxes associated with AD pathobiology across molecular, cellular, and biomarker levels. The hypothesis also highlights the limitations of current AD biomarkers and suggests new diagnostic and prognostic tools based on disease pathogenesis. Additionally, the framework identifies potential pharmacological targets for preventing disease progression.