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Inflammation Subsiding as a Suspect in Cognitive Disorders of Aging

The theory that inflammatory mechanisms are a prime target for prevention and treatment of aging-associated cognitive loss is weakened by two well-designed studies.

The theory that inflammation plays a primary role in the pathogenesis of Alzheimer disease (AD) has led to speculation that anti-inflammatory agents may be a fruitful area of research. We now have results from two randomized, double-blind, controlled studies of three different anti-inflammatory agents for the prevention of cognitive loss associated with age.

In the first study, investigators for the AD Anti-inflammatory Prevention Trial (ADAPT) compared 400 mg of celecoxib, 440 mg of naproxen, and placebo in 2125 individuals aged 70 or older who had a family history of AD. The study was terminated prematurely because of concerns about the safety of celecoxib; at that time, the rates of diagnosis of dementia did not differ significantly among the three groups. There was a trend toward more cognitive impairment in the treatment groups than in the placebo group. The authors speculate that perhaps these agents were not protective because they do not affect amyloid processing or because they were administered too late in the disease process.

The second study, embedded in the larger Women’s Health Study, was a randomized, double-blind trial; in one study arm, participants received aspirin (100 mg) or placebo every other day (results in a separate arm, 600 IU of vitamin E, were negative; see Journal Watch Neurology Apr 3 2007). Investigators used a cognitive battery covering five domains, administered by telephone at about 2-year intervals, to track more than 6000 women (mean baseline age, 72; average follow-up, almost 10 years). Overall, aspirin had no effect on cognitive decline. Secondary analyses suggested the possibility of a positive effect for aspirin in smokers and in participants with hyperlipidemia. Also, a small reduction in risk for decline in the category-fluency domain was reported for the aspirin group compared with placebo (relative risk, 0.80). The authors speculate that this finding might relate to an effect of aspirin on executive-function decline due to vascular disease.

Comment: These studies add weight to others that failed to demonstrate therapeutic effects of various anti-inflammatory agents (including steroids) on aging-associated cognitive decline. It is time to reconsider our treatment development strategies, recognizing that the biology of cognitive changes with age varies greatly, reflecting different genetic inheritances and, more important, lifetimes of different environmental exposures. Unrealistic expectations about developing magic bullets to address unhealthy brain aging distract us from emphasizing the therapeutic benefit of purposeful cognitive enhancement — through community engagement, physical exercise, and diet — in healthy brain aging.

— Peter J. Whitehouse, MD, PhD

Dr. Whitehouse is Professor of Neurology, University Memory and Aging Center, Case Western Reserve University, Cleveland.

Published in Journal Watch Neurology August 14, 2007

Citation(s):

ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 2007 May 22; 68:1800-8.

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• Medline abstract (Free)

Kang JH et al. Low dose aspirin and cognitive function in the women’s health study cognitive cohort. BMJ 2007 May 12; 334:987. (http://dx.doi.org/10.1136/bmj.39166.597836.BE)

• Original article (Subscription may be required)
• Medline abstract (Free)