Link between Aluminum and the Pathogenesis of Alzheimer′s Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses

TLDR

Aluminum, a ubiquitous environmental element, is a recognized neurotoxin that impairs numerous biological functions and has been implicated in neurodegenerative disorders, including Alzheimer’s disease, though its exact role remains unclear due to complex bioavailability. The study aims to reassess the connection between aluminum exposure and Alzheimer’s disease by integrating the aluminum and amyloid cascade hypotheses, focusing on β‑amyloid oligomerization and interactions with other metals. The authors review evidence that aluminum acts as a cross‑linker in β‑amyloid oligomerization and disrupts metal homeostasis, thereby exacerbating amyloid toxicity and contributing to Alzheimer’s disease pathogenesis.

Abstract

Whilst being environmentally abundant, aluminum is not essential for life. On the contrary, aluminum is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans. The relationship between aluminum exposure and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease (AD) has been suggested. In particular, the link between aluminum and Alzheimer's disease has been the subject of scientific debate for several decades. However, the complex characteristics of aluminum bioavailability make it difficult to evaluate its toxicity and therefore, the relationship remains to be established. Mounting evidence has suggested that significance of oligomerization of β-amyloid protein and neurotoxicity in the molecular mechanism of AD pathogenesis. Aluminum may play crucial roles as a cross-linker in β-amyloid oligomerization. Here, we review the detailed characteristics of aluminum neurotoxicity based on our own studies and the recent literatures. Our aim is to revisit the link between aluminum and AD and to integrate aluminum and amyloid cascade hypotheses in the context of β-amyloid oligomerization and the interactions with other metals.