The role of apoptotic pathways in Alzheimer's disease neurodegeneration and cell death.

Neuronal loss is associated with Alzheimer's disease (AD). However, it not clear what type of mechanisms underlie this neuronal loss and if neuronal loss is directly responsible for the progressive dementia of AD. This review summarizes the recent evidence for neuronal loss in AD relative to the level of cognitive impairment. It further describes the current evidence for an apoptotic mechanism in AD. Lastly, a summary of the evidence for synaptic loss being responsible for dementia rather than neuronal loss is presented. A novel hypothesis emerges from this data to explain all aspects of AD pathophysiology. This all inclusive hypothesis called the attrition hypothesis states that activation of the effector caspase-6 in AD due to one or a variety of insults is responsible for the breakdown of the cytoskeletal structure of neurites and damages proper trafficking of proteins and organelles thus resulting in the observed clinical and pathological features of AD.