Axons are lengthy projections of the cell body that connect neurons, essential to the function of the brain. Researchers here view what is known of the biochemistry of Alzheimer's disease through the lens of damage to axons. As they point out, the relentless focus on protein aggregation, particularly amyloid-β aggregation, in Alzheimer's disease does tend to crowd out more in-depth discussions of what it is that this protein aggregation actually does to cells.
Alzheimer's disease (AD) is the primary cause of dementia and is anticipated to impose a substantial economic burden in the future. Over a significant period, the widely accepted amyloid cascade hypothesis has guided research efforts, and the recent FDA approval of an anti-amyloid-β antibody, believed to decelerate AD progression, has further solidified its significance. However, the excessive emphasis placed on the amyloid cascade hypothesis has overshadowed the physiological nature of Aβ and tau proteins within axons.
Axons, specialized neuronal structures, sustain damage during the early stages of AD, exerting a pivotal influence on disease progression. In this review, we present a comprehensive summary of the relationship between axonal damage and AD pathology, amalgamating the physiological roles of amyloid-β and tau proteins, along with the impact of AD risk genes such as APOE and TREM2. Furthermore, we underscore the exceptional significance of axonal damage in the context of AD.