Autophagy impairment and Alzheimer's disease. (a) Schematic representation of the general steps of the autophagy pathway. (b) Ablation of the essential autophagy regulator Atg7 in neurons triggers spontaneous neurodegeneration, leading to the accumulation of ubiquitin-positive inclusions in a p62-dependent manner. Aggregate formation also involves the recruitment of partially phosphorylated Tau and active GSK-3β, resembling a 'pre-tangle' non-amyloidogenic state. (c) Speculative model: in Alzheimer's disease (AD), defects in the autophagy pathway due to genetic mutations, environmental factors and/or aging may contribute to the accumulation of abnormal protein aggregates and possible phospho-Tau on a pre-tangle state. For example, mutations in Presenilin-1 alter the pH of the lysosome, thus decreasing autophagy activity, which may enhance neurodegeneration and further accumulation of amyloid-β. Since during aging autophagy activity decreases over time, we speculate that autophagy impairment, together with other factors related to AD (genetic and environmental), may lead to a progressive flow from a pre-tangle to a neurofibrillary stage. This progression may be linked to the cognitive deficits associated with AD and tauopathies.