Summary

Alois Alzheimer made a major breakthrough when he discovered senile plaques in the brains of dementia patients, and his work ultimately led to the discovery of amyloid-β and to the amyloid cascade hypothesis. But that cascade is only part of a much bigger drama, and may even be one of the later acts. Researchers are still very much in the dark about what triggers amyloid buildup in most late-onset AD cases and what happens early in the lead-up toward AD.

Karl Herrup at Rutgers University, Piscataway, New Jersey, believes that the time has come to reassess what we know about AD, focusing less on amyloid and more on age-related changes that create the conditions for the disease to take hold. In a recent Disease Focus article in the Journal of Neuroscience, Herrup laid out a new model, of which the amyloid cascade is but one of many parts. His emphasis is less on amyloid and more on age-related changes that trigger pathology.

On 27 April 2011, this Webinar explored these ideas. Herrup presented his hypothesis and was joined for a panel discussion by Michael Heneka, University of Bonn, Germany; Dave Morgan, University of South Florida, Tampa; Mary Sano, Mount Sinai School of Medicine, New York; and Michael Wolfe, Brigham and Women’s Hospital, Boston, Massachusetts. Read the article, and submit your own ideas on Alzheimer’s etiology. The Alzforum editors gratefully acknowledge the Society for Neuroscience, which granted our readers open access to this article to facilitate discussion and stimulate new research directions.

Listen to the Webinar

Times:
Karl Herrup: 0:00
Michael Wolfe: 24:40
Michael Heneka: 35:12
Mary Sano: 43:51
Dave Morgan: 49:22
Discussion: 56:13

Karl Herrup's Presentation

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Michael Wolfe's Presentation

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Michael Heneka's Presentation

Mary Sano's Presentation

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Dave Morgan's Presentation

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Background

Background Text
By Tom Fagan

The identification of amyloid-β peptides in senile plaques was a major breakthrough in Alzheimer’s research, and ultimately led to the amyloid cascade hypothesis. That hypothesis contends that accumulation of Aβ is the major driving force in AD pathology. The theory also became a major driving force in AD research, leading to a wealth of new information. But roughly over10 years later, researchers are still trying to get a handle on what causes most cases of Alzheimer’s disease. For rare, inherited forms that are driven by mutations in amyloid precursor protein or the presenilins that cleave amyloid-β from it, the cause is clear. But for the vast majority of late-onset cases, the trigger remains uncertain.

The strongest risk factor for late-onset AD, by far, is age. In his article in the Journal of Neuroscience, Herrup argues that the etiology of the disease should be considered in that context. Age brings a slowing of cognition, a deterioration in motor function, a loss of synaptic complexity in the brain, and a weakening of immune defenses, all of which could set the stage for subsequent neurodegeneration. How does a signature pathology of Alzheimer’s emerge from this state?

Herrup cites hip fracture as a useful analogy. There are many risk factors that lead to hip fractures—weakening bones due to osteoporosis, loss of muscle control and strength, poor balance, slower reaction time, and weakening visual acuity. None of these by themselves cause hip fracture, but they set the stage for an event that does, such as a fall. Is something similar going on in the aging brain? Herrup hypothesizes three steps that ultimately lead to AD: an initial injury, an ensuing chronic inflammatory response, and a change in cellular state that affects most of the brain. The initial injury could be a head trauma or a cardiovascular failure, such as a micro-stroke. The change in state could be an attempted re-entry into the cell cycle—a no-no for post-mitotic neurons—or an irreversible activation of microglia. These events would, in turn, set the stage for accumulation of Aβ and for neurodegeneration.

What does this view mean for the study, prevention, and treatment of Alzheimer’s? Herrup suggests that if the initial injuries can be identified, then it may be possible to intervene early to delay disease onset. A refocus on aging as the major risk factor might spur new therapeutic approaches that capitalize on recent insights into the aging process. And the realization that cells are changing could lead to a re-evaluation of the molecular biology surrounding Aβ, tau, autophagy, and other key players and processes that have been implicated in pathology. To understand Herrup’s perspective beyond these brief excerpts, Read his article in the Journal of Neuroscience, and then bring your comments to the table.