The concept of redox balance in Alzheimer's disease: Mark Anthony Smith 1965–2010

On December 19, 2010, Mark A. Smith was tragically and instantly killed when hit by a car while walking home from a nearby holiday party. When Mark came on the oxidative stress scene 20 years ago, he followed on the pivotal work of Earl Stadman, Robert Floyd, William Markesbery, and Flint Beal to place oxidative stress as a pillar of disease pathogenesis. He accomplished this task by means of a multi-pronged approach: innovative methods and concepts, collaboration with numerous investigators, and, most strikingly, with an eye for fundamental flaws in any hypothesis, including his own.

In the early work he demonstrated oxidative modification of every category of biological macromolecule: protein, carbohydrate, lipids, and nucleic acids. But it was Mark's rapid comprehension that oxidative damage is countered by an antioxidant response that bound his ideas. Coincident with pathology he reported protective responses: inducible heme oxygenase, stress kinases, NQO1, sulfhydryl reduction, and cell cycle re-entry. These findings defined a new concept in oxidative stress, one of homeostasis where radicals do not breach defenses, but a new balance is reached designed to protect cells from death. Marks's work on neuronal death changed the view of neuronal apoptosis; rather than dying, neurons in Alzheimer's disease (AD) resist death through induction of many of the pathways linked to apoptosis, but without completion of the death response.

Mark fundamentally had a distrust of any mechanism that did not rely on biological adaptation for successful aging. Amyloid-β, tau, oxidative stress, and other AD mechanisms recapitulate the response of the brain to injury: trauma and aging are both met by the same responses defining AD. Instead, his efforts were to connect AD to physiology, leading to the two-hit hypothesis¹ and other theories, which all focused on the pleotropic threshold between pathology and physiology. The foundation of Mark's contribution is in stark contrast to the amyloid-β, tau, or any other pathology-based theory. His focus was on physiology as the route to understand and reverse the disease process. It was not long before Mark proposed that pathological changes were critical homeostatic responses to AD rather than the cause. Further, it is not surprising that Mark suggested over a decade ago the failure of the amyloid-β vaccine^2,3 based on its potential to disturb the balance of a critical biological response to the underlying pathogenesis of AD. Mark's ideas explain why we have failed to cure chronic disease after a century of success curing acute disease; diseases in which a new protective balance is achieved versus those of disastrous imbalance. The miracle of AD is that neurons filled with tau and in an environment inundated by amyloid-β can live for decades – not that they may eventually succumb. Working with the physiology to modulate the response of aging and restoring normal balance offers greater hope for additional years of health. Mark focused much of his last efforts in this quest.

He was the most prolific author in AD research over the past 10 years, and the fifth most cited (http://sciencewatch.com/ana/st/alz2/authors/). In addition, he won numerous awards including the Jordi-Folch award from the American Neurochemistry Society, Hermann-Esterbauer Award from the HNE Society, the Outstanding Investigator Award from the American Society for Investigative Pathology, Denham Harman Research Award from the American Aging Association, and the Goudie Lecture and Medal from the Pathological Society of Great Britain and Ireland. He was a fellow of the American Association for the Advancement of Science, American Aging Association, Royal Society of Medicine, and the Royal College of Pathologists. His greatest pride was service, ranging from Editor-in-Chief of the Journal of Alzheimer's Disease, Executive Director of the American Aging Association, organizer of numerous meetings, participant in many National Institutes of Health, Veterans Administration, and other grant reviews, and member of over 200 editorial boards including this journal. It is no surprise that several societies have either named their own rising investigator awards after Mark, or dedicated meetings, books, and journal issues to his memory. The outpouring of remembrance from AD researchers throughout the world has been astounding, so many saying that Mark's courage to deliver a message as he saw it was an inspiration in their own lives (http://www.j-alz.com/marksmith.html).

That Mark was the origin of a novel view of disease is not surprising, because he was tied to family values of hard work and honesty learned from his coal miner father. His focus was always on what he could give to those affected by disease, or to those studying and working with him, rather than on personal benefit. Mark leaves a science family that spans almost every continent.

Those he touched will continue to be inspired by Mark's courage to trust scientific observation, by his creativity in developing novel hypotheses with courage, and by his great generosity to friends and colleagues.