30 July 2007. Two potential treatments for Alzheimer disease—the nonsteroidal anti-inflammatory drugs (NSAIDs) and ginkgo biloba—are the subject of several papers this week.
The twisting path to prevention for Alzheimer disease is nowhere more apparent than in the saga of the NSAIDs, a tale of promise and setback. Epidemiological studies support an association of NSAID use with a lowered risk of AD, and the biological rationale is in place—the drugs quell inflammation and appear to reduce the production of toxic amyloid-β1-42 peptides (see ARF related news story). However, a prospective clinical trial aimed at establishing whether the medicines could slow progression of AD was halted in 2004 amidst concerns over cardiovascular effects of the drugs (see ARF related news story). With the route to definitive results cut off, how are researchers to proceed?
One avenue is to continue accumulating epidemiological information on the drugs. Researchers carrying out the large observational study in Cache County, Utah, are doing just that, and have published their latest data in the July 25 issue of Neurology. Their analysis indicates that NSAID use is associated with slower cognitive decline, but only in a select group of people. First author Kathleen Hayden of the Duke University Medical Center in Durham, North Carolina, and the Cache County Investigators present an analysis of 3,383 elderly residents who were followed with cognitive testing for between 3 and 8 years. People who carry the ApoE ε4 allele, a genetic risk factor for AD, and those who started to use the medicines early (before age 65) had a lower rate of decline than others had in the study.
The differences in the rates of decline are very small, just a fraction of a point per year on the Modified Mini-mental State Exam, and so their practical impact is open to debate. However, as the authors point out, even if the changes delay entry into a nursing home for a few months, that could have a profound effect society-wide. A bigger concern with the study, and a caveat of all observational studies, is whether unrecognized factors relating to cognitive decline and/or NSAID use are actually causing the observed differences (see comment below from Paul Aisen).
In an editorial accompanying the paper, Jeremiah Scharf and Kirk Daffner of the Brigham and Women’s Hospital in Boston, Massachusetts, address the important question, what are doctors and patients to do with this new information?
“Clinicians trying to weigh the risks and benefits of NSAIDs in AD prevention face a Catch-22 (or, in this case a ‘Cache-22’),” Scharf and Daffner write. “In order to quantify the risks of NSAID use, one needs data from a primary prevention trial. However, such a trial is unlikely to occur, because it is currently thought to be too risky.” With further work to define the risks and benefits, they write, there may emerge a group of individuals with a profile warranting a focused, randomized control trial. Until then, they conclude, “It is prudent for clinicians to refrain from recommending NSAIDs for use in AD prevention.”
For ginkgo, the path ahead looks more clear-cut. Ginkgo has been used for centuries in Asian cultures as a memory enhancer. A standardized extract (EGb-761) is currently the subject of two clinical trials for Alzheimer disease (DeKosky et al., 2006; Vellas et al., 2006). The chemical complexity of the mixture, and its multiple effects as an antioxidant, a phosphodiesterase inhibitor, and a modulator of Aβ production and toxicity, has stimulated efforts to both understand its actions, and define the exact chemical entities responsible for these pharmacological effects.
Enlisting modern science to try and improve an ages-old folk medicine, Michael Shelanski and colleagues at Columbia University in New York are taking a divide-and-conquer approach. Writing in the July 17 issue of Neurobiology of Aging, first author Ottavio Vitolo and coworkers report that a ginkgo fraction enriched for the ginkgolide and bilobalide terpene trilactone compounds, both minor components of the original extract, prevents the synaptic toxicity of amyloid-β. They identify specific ginkgolide fractions (J and A) that most effectively reverse Aβ-induced inhibition of long-term potentiation in mouse hippocampal slices. However, they find that only the J fraction inhibits cell death induced by treating cultured neurons with high concentrations of Aβ. They conclude, “This beneficial and multi-faceted mode of action of the ginkgolide makes it a new and promising lead in designing therapies against Alzheimer’s disease.”
Their results jibe with previous findings that ginkgolide fractions A and J suppress Aβ pathology in transgenic worms (see ARF related news story). The new work provides further support for the idea that the beneficial effects of ginkgo might stem from direct interference with Aβ toxicity, rather than a generalized antioxidant or other effect.—Pat McCaffrey.
Hayden KM, Zandi PP, Khachaturian AS, Szekely CA, Fotuhi M, Norton MC, Tschanz JT, Pieper CF, Corcoran C, Lyketsos CG, Breitner JC, Welsh-Bohmer KA; Cache County Investigators. Does NSAID use modify cognitive trajectories in the elderly?: The Cache County study. Neurology. 2007 Jul 17;69(3):275-82. Abstract
Scharf JM, Daffner KR. NSAIDs in the prevention of dementia: a Cache-22?
Neurology. 2007 Jul 17;69(3):235-6. Abstract
Vitolo O, Gong B, Cao Z, Ishii H, Jaracz S, Nakanishi K, Arancio O, Dzyuba SV, Lefort R, Shelanski M. Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide. J. Neurobiol Aging. 2007 Jul 17; [Epub ahead of print] Abstract