Figure 1

The Amyloid Hypothesis. The amyloid hypothesis postulates that Aβ aggregation triggers a cascade of events ultimately resulting in AD. Familial mutations in PSEN1, PSEN2 or APP are associated with early-onset AD (EOAD). These genetic risk factors are postulated to impact the cleavage of Aβ from APP, leading to oligomerisation and eventual Aβ plaque formation. Individuals with trisomy 21 (Down’s Syndrome), and therefore a triple copy of APP, suffer EOAD. The strongest genetic risk factor for late-onset AD (LOAD) is the presence of at least one APOE4 allele. It is unclear as to what triggers Aβ accumulation in LOAD, though it is suggested that there may be a number of contributing factors such as reduced Aβ clearance due to APOE genotype. Aβ oligomerisation is proposed to trigger a cascade involving the formation of neurofibrilliary tangles (NFTs) composed of hyperphosphorylated tau, synapse loss, neuron death and widespread neuroinflammation, particularly in brain regions involved in learning and memory, such as the hippocampus. As the amyloid burden increases, the ongoing catastrophic loss of synapses and neurons is thought to lead to progressive dementia.