Imagine a bustling city with multiple transportation routes. The roads and highways are crucial for connecting different neighborhoods and ensuring the smooth flow of goods and people. Similarly, within our brains, axons serve as the ‘roads’ that enable communication between neurons. In Alzheimer’s disease, these vital axons suffer damage early on, significantly impacting the progression of the disease. While much attention has been given to the amyloid cascade hypothesis, researchers are uncovering the immense importance of axonal damage and its relation to key proteins like Aβ and tau. This comprehensive review provides a deeper understanding of the physiological roles of these proteins within axons and highlights the influence of genetic risk factors like APOE and TREM2. It sheds light on the often overlooked significance of axonal damage in Alzheimer’s disease, offering new avenues for exploration and potential therapeutic strategies.

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-beta (Aβ) protofibrils 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 Aβ 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.

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