Alzheimer’s Disease Research: Where to Next?

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Dennis Selkoe, MD, discusses progress and problems in recent research on this enormously common and devastating disorder in a Perspective in Nature Medicine.

In a special perspective piece published in Nature Medicine, Dennis Selkoe, MD, a leader in the global fight against Alzheimer's disease (AD), discusses progress and problems in recent research on this enormously common and devastating disorder. He addresses misunderstandings and concerns in the AD field and then offers possible explanations for the failure of some recent research trials and describes opportunities for success in the not-too-distant future.

"Despite dramatic progress since the 1960's, the field of Alzheimer's research has entered a period of disappointment and concern about the path forward," said Selkoe, co-director of the Center for Neurologic Diseases at Brigham and Women's Hospital. "In the context of the recent failure of some late-stage clinical trials, much can be learned from them about how to better develop safe and effective treatments, including some that are already in testing."

First, Selkoe clarifies some controversies about the nature of AD. He summarizes the evidence to date relative to the "amyloid hypothesis"; explains the significance of amyloid beta-protein (Aß) deposits in healthy brains; offers a concept of amyloid as both a cause and an effect of AD; and addresses questions regarding small Aß aggregates ("oligomers") vs. large amyloid plaques by suggesting it is not either/or, but both, that are significant. Selkoe emphasizes the importance of both continuing to identify drugs that can bind to Aß and alter its cellular effects and also searching for drugs that neutralize the tau protein which makes up the tangles of AD. He brings together two previously separate camps of AD researchers, "BAPtists" and "TAUists", by citing evidence that both types of protein changes have a role in inducing dementia together. Selkoe also outlines criteria for the better development of animal models to assess potential AD treatments.

Next, Selkoe addresses the widely reported failures of certain experimental drugs that aimed to lower the Aß protein in the brain and argues that positive lessons can be learned from these trials and they are not indicative of what can be expected in the future.

"A close examination of these failed phase 3 clinical trials provides no evidence that the target was the problem, but rather that specific drugs were highly flawed," he said.

According to Selkoe, to ensure success in the near to intermediate future, the mechanism of a drug's action and its efficacy must be more thoroughly tested in appropriate cell and animal models before initiating human clinical trials. Equally important is conducting those trials in subjects who are mildly affected or even pre-symptomatic. The potential to impact AD, as in other chronic diseases such as cancer, hypertension and diabetes, is greatest with early intervention. And based on recent progress on all these fronts, the possibility of success before too long is now palpable.

RELATED LINKS
Center for Neurologic Diseases at Brigham and Women's Hospital
Selkoe Laboratory at Brigham and Women's Hospital

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