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.

Cite this article as: Sönmez G, Yazarkan Y, Erden Aki O, Bodur E. Unraveling the enigma: exploring the periphery’s influence in Alzheimer’s pathophysiology—cause or consequence? Eurasian J Med. 2025, 57(1), 0592, doi: 10.5152/ eurasianjmed.2025.24592.