Unraveling the Enigma: Exploring the Periphery’s Influence in Alzheimer’s Pathophysiology—Cause or Consequence?

Alzheimer's disease (AD) remains a formidable challenge, impacting individuals, families, caregivers, and soci- ety. Despite being identified over a century ago, effective drug treatments for AD remain elusive, with numerous clinical trials failing to produce meaningful results. The pathological hallmarks of AD, including the accumulation of beta-amyloid plaques and tau protein tangles, are well-established contributors to cogni- tive decline. However, recent research has raised questions about the efficacy of therapies targeting these abnormalities. Emerging evidence suggests that AD should not be viewed purely as a brain-centered disease but as a systemic condition involving complex interactions between the brain and peripheral organs. While the mechanisms linking peripheral processes and AD pathology remain unclear, studies indicate that these systems may contribute to or be affected by the disease. Recognizing AD as a heterogeneous disorder with systemic implications opens new opportunities for therapeutic innovation. Multimodal therapies targeting both central and peripheral aspects of AD pathology-such as amyloid-beta deposition, neuroinflammation, and systemic dysfunction-hold promise for slowing disease progression. This review aims to critically assess the current understanding of AD pathology, with a particular focus on the peripheral system's involvement and its interplay with the brain. Additionally, it will explore novel therapeutic strategies and emphasize the importance of interdisciplinary collaboration to advance our knowledge and develop effective treatments.