Trials and Treatments: New Results Highlight Would-be AD Medicines

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

Comments

  1. This paper from the Cache County Investigators reports an association between long-term NSAID use and slow cognitive decline on the 3MS in individuals who started NSAIDs at a young age and carry the ApoE4 allele. As the authors point out, though the findings are interesting, this is an observational study that cannot yield conclusive evidence of a neuroprotective effect. Further, the randomized study necessary to demonstrate such an effect would be essentially unfeasible. So we are left with intriguing results that should not be used to guide treatment recommendations. In fact, since almost all randomized controlled trials suggest that any effect of NSAIDs on neurodegenerative disease is more likely harmful than beneficial, it may be reasonable to attribute the apparent protective effects reported here to biases that could not be fully controlled for in the analyses. Perhaps there are biological, cognitive, behavioral, or socioeconomic factors linked to long-term NSAID use that influence likelihood of cognitive decline.

    View all comments by Paul Aisen
    • User Profile Image Yuan Luo
      University of Maryland
    • Posted:

    The current available drugs for Alzheimer disease (AD) only confer modest benefits. Additional AD therapies are urgently needed. Ginkgo biloba leaf extract, EGb 761, has been used as a dietary supplement in the U.S. for Alzheimer dementia. Several clinical trials have provided evidence of efficacy comparable to donepezil (Mazza et al., 2006) for treatment of mild to moderate AD. The evidence for EGb 761 enhancing learning in healthy humans is inconclusive (LaBar et al., 1997; Solomon, et al., 2002). A well-controlled study supported by the NIH is underway (DeKosky et al., 2006). Although the extract EGb 761 has been substantially studied at all levels of biological systems (Christen, 2002), its neuroprotective mechanisms and pharmacological evaluation of the active components remain puzzling to the scientific community. Two major constituents of EGb 761, flavonoids (24 percent) and terpenoids (6 percent) have been actively investigated (DeFeudis, 1998). The terpenoid fraction primarily contains ginkgolides A, B, C, J, and M, and bilobalide, which are specific to the ginkgo biloba tree (Nakanishi, 2005). The ginkgolide B is known as a potent antagonist of platelet activating factor receptor (PAFR) (Smith et al., 1996). The flavonoids impart antioxidative properties to EGb 761. In this paper, Ottavio Vitolo and colleagues in Michael Shelanski’s laboratory reported a very elegant study demonstrating that a terpene trilactone-enriched EGb 761, P8A, completely blocked Aβ-induced LTP reduction and neuronal cell death, two systems that have been considered to be related to AD. A single constituent of EGb 761, ginkgolide J, exhibited the most potent effect on LTP among other EGb 761 components. This observation is consistent with a previous finding that ginkgolide A and J alleviated Aβ-induced pathological behaviors in a C. elegans model (Wu et al., 2006) and enhanced adult neurogenesis and phosphorylation of CREB in a mouse model of AD (Tchantchou et al., 2007). The novelty of this study is that they employed LTP or long-term potentiation, a well-accepted, sophisticated cellular model for neuroplasticity, to investigate a challenging question of complexity. Their results provided initial identification of the key compounds of the extract that affects synaptic function, and provided the rationale for future medicinal chemistry studies based on the chemical structures derived from the extract. The use of mouse hippocampus slices allows for screening of compounds that target at early synaptic and cognitive changes in relation to AD. Compound(s) identified in this model could implicate potential enhanced efficacy of ginkgolide J to the mammalian model of AD and clinical studies. The unique structure of ginkgolides, their bioavailability, combined with its effects on synaptic dysfunction demonstrated by Vitolo et al. (2007) makes them a promising source of novel therapeutic candidates. Neurotoxicity and the natural resource of ginkgolide J is the next issue to be addressed.

    See also:

    DeFeudis, F.V., Ginkgo biloba extract (EGb 761): from chemistry to clinic. 1998: Publi Ullstein Med. Weisbaden, Germany.

    References:

    Mazza M, Capuano A, Bria P, Mazza S. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006 Sep;13(9):981-5. PubMed.

    Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997 Oct 22-29;278(16):1327-32. PubMed.

    Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R. Ginkgo for memory enhancement: a randomized controlled trial. JAMA. 2002 Aug 21;288(7):835-40. PubMed.

    Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.

    Christen Y, Maixent JM. What is Ginkgo biloba extract EGb 761? An overview--from molecular biology to clinical medicine. Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):601-11. PubMed.

    Nakanishi K. Terpene trilactones from Gingko biloba: from ancient times to the 21st century. Bioorg Med Chem. 2005 Sep 1;13(17):4987-5000. PubMed.

    Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol. 1996 Mar;50(3):131-9. PubMed.

    Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13. PubMed.

    Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J. 2007 Aug;21(10):2400-8. PubMed.

    View all comments by Yuan Luo

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References

News Citations

  1. Anti-inflammatory Drugs Side-Step COX Cascade to Target Aβ
  2. Safety Concerns Halt ADAPT Trial
  3. Ginkgo Biloba—Antioxidant Plus Oligomer Buster in Worms

Paper Citations

  1. Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R, Furberg C, . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006 Jun;27(3):238-53. PubMed.
  2. Vellas B, Andrieu S, Ousset PJ, Ouzid M, Mathiex-Fortunet H, . The GuidAge study: methodological issues. A 5-year double-blind randomized trial of the efficacy of EGb 761 for prevention of Alzheimer disease in patients over 70 with a memory complaint. Neurology. 2006 Nov 14;67(9 Suppl 3):S6-11. PubMed.

Further Reading

Primary Papers

  1. Scharf JM, Daffner KR. NSAIDs in the prevention of dementia: a Cache-22?. Neurology. 2007 Jul 17;69(3):235-6. PubMed.
  2. 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, . Does NSAID use modify cognitive trajectories in the elderly? The Cache County study. Neurology. 2007 Jul 17;69(3):275-82. PubMed.
  3. 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. 2009 Feb;30(2):257-65. PubMed.

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