Experts Weigh in on Developing Drugs to Delay "Normal" Cognitive Decline

Marlene Busko

March 06, 2009

March 6, 2009 — Researchers may someday develop drugs to stave off normal, age-related memory loss, but this work should not be done at the expense of Alzheimer's disease (AD) research, experts say.

These and other scientific, legal, and ethical issues surrounding the development of drugs that target normal cognitive decline were discussed in a February 26 Webinar presented by the Alzheimer Research Forum, a nonprofit organization.

The session featured 3 researchers, a legal expert, and a member of the United States Food and Drug Administration (FDA).

Delaying Normal Decline

Only recently has research shed light on subtle differences between normal aging and early AD. For example, preliminary research suggests early AD targets the entorhinal cortex, whereas normal aging targets the dentate gyrus.

Recent animal and human studies conducted by Scott A. Small, MD, from Columbia University, in New York, and colleagues show age-related increases in blood glucose target the dentate gyrus. Their findings suggest that physical exercise, diet, or drugs to improve glucose metabolism may help avert a decline in cognitive ability.

Other research has examined how defects in histone acetylation may be involved in cognitive decline.

"As we are living longer and have dealt with mortality and morbidity, and as we want to live cognitively engaging and enriched lives, I do think . . . we should at least consider developing therapeutic interventions for age-related memory decline," said Dr. Small.

This is not the same as developing "smart drugs," or memory enhancers, he cautioned. "We're not talking about boosting memory above normal. We're talking about developing therapeutic interventions to prevent and stave off a worsening of our baseline as we age."

The drugs would need to be proven safe in a healthy population, and the studies should not siphon off resources from research to develop a potential cure for AD, he said.

Legal and Ethical Issues

"Overall, I wish Scott and colleagues a lot of luck," said Henry T. Greeley, a legal ethicist from Stanford University, in Palo Alto, California. "I look forward to their success. I think society should welcome it, but there are some issues to be concerned about."

First, it is not clear whether such drugs would enhance normal cognition or treat a pathological condition. If the drugs are very expensive, insurance companies may balk at covering them, he noted.

In addition, memory-enhancing drugs would still need to be proven safe and effective in healthy individuals. Furthermore, making the best use of limited research resources is essential, and research into memory-improving drugs should not come at the expense of neglecting AD research.

Finally, said Mr. Greeley "the possibility of widespread, off-label use — some of it black-market, off-prescription use by populations on whom the drugs have not been tested — is a real, serious concern," he said.

AD Drugs Harm Healthy Individuals

"We have to be very careful," John (Wes) Ashford, MD, also from Stanford University, concurred.

"Before we advocate for the addition of any substance to be added for routine use . . . there should be extensive evidence of exactly whom it helps, how much it helps, and what the costs and adverse effects are, particularly over very long periods of time," he said in a statement posted on the Alzheimer Research Forum Web site.

"There is no evidence that any medication for people with AD helps individuals without dementia," he added.

Trials of AD medications in individuals with mild cognitive impairment (MCI) have been negative or have shown numerous adverse effects.

Cholinesterase inhibitors appear to be severely addictive.Patients who discontinue these drugs exhibit a steep decline in cognition. Similarly, memantine has been shown to help only patients with moderate to severe dementia and can be harmful in patients with mild dementia.

Future research should investigate the relationship between apolipoprotein E subtypes and AD pathology, including how dietary adjustments might delay development of AD, he said.

Lifestyle Factors

A recent study showed that moderately obese individuals who had a 30% caloric restriction improved their performance in recall tests, said Samuel Gandy, MD, from Mount Sinai School of Medicine, in New York.

This suggests that many people might have suboptimal memory as a consequence of their dietary habits.

"If diet and metabolic factors are playing such an important role, especially with the expanding epidemic of obesity, perhaps we should pay attention not only to the cardiovascular threat of obesity but also to the cognitive thereat," he said.

"Lifestyle factors — though often discounted — may be our best route and should not be overlooked in terms of optimizing cognition," he said.

Regulatory Considerations

For a drug to be approved, the proposed treatment has to have a measurable clinical benefit that matters to people, said Russell Katz, MD, from the division of neuropharmacological drug products at the FDA Center for Drug Evaluation and Research, in Rockville, Maryland.

However, he added, approval of a drug intended to treat otherwise-normal people would have to have very clear evidence of safety and would require long-term study with a large sample size.

Alzheimer Research Forum. Presented February 26, 2009.

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