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

## TL;DR

This paper reviews Alzheimer's disease as a systemic condition involving interactions between the brain and peripheral organs, suggesting new therapeutic strategies.

## Contribution

The paper emphasizes the novel perspective of Alzheimer's as a systemic disorder involving peripheral systems, not just a brain-centered disease.

## Key findings

- Emerging evidence suggests Alzheimer's disease involves complex interactions between the brain and peripheral organs.
- Targeting both central and peripheral aspects of AD pathology may offer new therapeutic opportunities.
- Current therapies focusing solely on brain pathology have had limited success, highlighting the need for systemic approaches.

## Abstract

Alzheimer’s disease (AD) remains a formidable challenge, impacting individuals, families, caregivers, and society. 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 cognitive 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.