The molecular pathology of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people, and the fourth most common cause of death in developed nations. Clinically, the disease is characterized by the deterioration of a patient’s cognitive and functional abilities, which may be accompanied by varying degrees of psychiatric and behavioural symptoms. The clinical decline is associated with a significant loss of neurons and synapses and ensuing neurochemical changes within the brain of an affected individual. In addition, two further microscopic pathologies are observed within the brain tissue: extracellular neuritic plaques and intracellular neurofibrillary tangles (NFTs). Both of these distinctive neuropathologies, regarded as hallmarks of the disease, are the result of abnormal aggregation of proteinaceous material. Neuritic plaques are largely formed from the aggregation of the 4 kDa β-amyloid peptide, which is released into the extracellular space following the metabolic breakdown of the larger amyloid precursor protein (APP). NFTs, which develop within neurons, are aggregates principally composed of the cytoskeletal protein tau and may be initiated by aberrant phosphorylation of tau. The prevailing view within the field is that mismetabolism of APP and abnormal production, aggregation and deposition of Aβ are central to the pathogenesis of AD, and that the Aβ pathology somehow leads to the tau/NFT pathology and the subsequent neuronal damage observed. In this article we review our current understanding of these molecular events and highlight how this knowledge is directing approaches to develop AD-modifying therapies.