Alzheimer’s disease (AD) is a devastating condition and its causes are still largely unknown. Various metals have been implicated as possible contributors to the development of AD. In a special double issue of the Journal of Alzheimer’s Disease published in November 2006, guest editors Andrei C. Miu and Oana Benga have brought together 14 insightful articles that explore the roles that metals play in the biochemistry and physiology of AD.

The articles cover six major categories: Comprehensive historical reviews, methodological perspectives, a topical review, integrative genetic and epigenetic reports, a review of risk factors and a “benchmark to clinical” review.

From guest editors Andrei C. Miu and Oana Benga: “We are grateful to the authors who accepted our challenge and who have shown that metallobiologists working in AD research have been less fascinated with describing end-stage pathognomonic lesions, and more concerned with identifying risk and aggravating factors that might help us better predict, diagnose and hopefully prevent AD in the future.”

John Savory, Mary M. Herman and Othman Ghribi review the four-decades-old controversy about aluminum neurotoxicity, examining data on the possible cellular mechanisms underlying aluminum neurotoxicity and potential neuroprotective strategies against aluminum toxicity. In the next review, Paul A. Adlard and Ashley I. Bush discuss how metal ions such as zinc and copper can potentiate Alzheimer’s disease by participating in the aggregation of normal cellular proteins and in the generation of reactive oxygen species. In the third review article, Arezoo Campbell focuses on how aluminum and copper can initiate or propagate an inflammatory response in the aging brain. Christopher Exley reviews in-vitro studies of metals found in plaque cores in AD brains and concludes that aluminum and iron could cause oxidative damage but copper and zinc likely do not. In the final review article, Andrei C. Miu and Oana Benga recount the long history of aluminum’s hypothetical role in AD. They extensively discuss several lines of evidence for involvement of aluminum as a secondary aggravating factor or risk factor and argue that further studies are warranted.

Bettina Platt discusses the methodologies that have been used to identify Alzheimer- and dementia-related targets for exogenous toxins. She explains how neuronal function can be assessed experimentally, based on the evidence obtained for the neurotoxin aluminum. In the second article on methods, Joanna Collingwood and Jon Dobson write about recent approaches to locate and identify iron compounds in neurodegenerative tissue. In addition to complementary techniques that allow them to quantify and identify iron compounds using magnetometry, extraction and electron microscopy, they utilize a powerful combined mapping/characterization approach with synchrotron X-rays.

The movement of metals across the blood-brain barrier is reviewed by Robert A. Yokel. A number of transporters are described that could mediate metal transport into and out of the brain. He reviews the role of these transporters in moving aluminum, manganese, iron and other metals across the blood-brain barrier.

Hani Atamna has developed a novel model of amyloid-beta induced heme-deficiency that could account for neurodegeneration in AD patients. He reviews the genetic, nutritional and toxicological factors that influence heme metabolism and their relevance to AD. James R. Connor and Sang Y. Lee discuss genetic mutations in the HFE gene that can affect iron balance in the brain, potentially leading to the generation of reactive oxygen and oxidative damage. In a study of the presenilins (PS), Nazneen N. Dewji discusses how these proteins can trigger a cascade of processes that lead to amyloid-beta production, leading to AD. He reviews the structures of the PS proteins that can support the model of a surface reaction between two nearby brain cells. Iftach Dolev and Daniel M. Michaelson write about the apoE4 isoform of apolipoprotein E. Their study of the nucleation, growth and reversibility of amyloid-beta deposition in mice should shed new light on this genetic risk factor for AD.

Vincenzo Solfrizzi and co-authors review the possible role of macronutrients and the basic elements of carbohydrates, proteins, and fat in the development of AD. They suggest that healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defense against the development and progression of cognitive decline.

In the final article, Jose L. Domingo focuses on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of aluminum, copper and zinc chelating agents on amyloid-beta plaques are reviewed.

Special Issue: Metals in Alzheimer’s Disease