Pathways to Pathology—The Amyloid Hypothesis

Research over the last 20 years has led to a better understanding of the basic biology of plaque and tangle formation. These findings, along with genetic evidence, strongly support the “amyloid hypothesis” as the leading theory for the cause of AD.[19, 21]

Figure 7. The process leading to amyloid plaque formation, neuronal loss, and AD.[23]

According to this hypothesis, it is altered production, aggregation, and deposition of the amyloid beta (Aβ) protein that results in amyloid plaque formation. This process initiates a cascade of pathological events leading to neuronal loss, impaired cell-to-cell communication, and ultimately the cognitive and behavioral dysfunction of AD.[19, 22]

Amyloid plaque formation begins with the amyloid precursor protein (APP), a protein that is embedded in the cell membrane. In neuronal cells, APP can be processed by multiple pathways—one of which leads to development of AD. In this pathway-to-pathology, APP is cut first by the enzyme β-secretase and then by gamma-secretase to form Aβ fragments of varying lengths. The fragment of most interest is the peptide known as Aβ42. It is the accumulation and aggregation of the toxic Aβ42 fragment that triggers a host of downstream processes that lead ultimately to neuronal cell death and AD (Figure 7).[19, 21, 23, 24]