We'd all like to escape dementia in our old age. Over the past decade, numerous large scale epidemiological studies have been published singing the praises of a variety of agents that might prevent or delay dementia. Of course, ever since the recent estrogen debacle, in which early promising observational findings were completely overturned by a well-designed clinical trial, we are all a little reluctant to believe what the epidemiologists are telling us. Nonetheless, we have to work with the data that we have, and here it is.

NSAIDs. Since much of the cell destruction in AD may be related to inflammatory processes, an anti-inflammatory may be helpful in slowing the progression. The first indication that this might be true came from the curious finding that people with rheumatoid arthritis tended not to become demented. Medication-wise, what separates these patients from everyone else? The use of non-steroidal anti-inflammatories (NSAIDs).

Since then, large observational studies have been conducted. The usual method is to identify a large number people in the community, to ascertain how many of these people took NSAIDs and for how long, and then to find out which patients developed AD, either by looking at their charts or interviewing them. You don't have to be a research whiz to see that this method is vulnerable to serious problems. For example, these studies may not have ascertained exactly which NSAIDs were taken, what the doses were, or exactly how long they were taken, all of which are good things to know when you are advising your patients.

Nonetheless, a recent large study from the Netherlands (1) was better designed than most, and has convinced many in the research world that NSAIDs are probably protective against AD, but only if they are taken for at least 2 years straight. Patients who were on NSAIDs for at least two years were only 20% as likely to develop AD as those who were NSAID free.

The Memantine Story
No, contrary to all appearances, memantine is not yet FDA approved for dementia. A spate of Forest-funded journal supplements and CME-Inc courses are apparently aimed at whetting our appetites, but they are about 6 months early. Memantine is an NMDA antagonist, and tries to prevent too much glutamate from pounding neurons already surrounded by beta-amyloid glue. The studies so far show modest efficacy, no better than the AchEIs, (and no better for severe dementia than AChEIs.) One study finds it to be an effective adjunct to Aricept, and this plus its good side effect profile will likely make it popular.

Vitamin E. Don't tell me you didn't start prescribing megadoses of vitamin E to your elderly patients after the famous NEJM article of 1997 (2). Yes, I'm talking to you!

We all did, because that data appeared so compelling, and vitamin E appears so harmless. To refresh your memory, that was the study in which 341 moderately demented patients with AD were randomly assigned to 2000 International Units (IUs) of vitamin E, 10 mg/day of selegiline, the combination of the two, or placebo. Compared to placebo, vitamin E delayed a bad functional outcome by 230 days-not bad for something you can pick up at your neighborhood General Nutrition Center. While a few other similar studies have modestly supported a protective effect of vitamin E, a recent fancy meta-analysis of a range of antioxidants (including vitamin E) found that they were of absolutely no benefit in the prevention of a different entity-cardiovascular disease (3). And while dementia is something entirely different, this finding has deflated everyone's enthusiasm for prescribing vitamins for the prevention of major disorders.

Ginkgo Biloba. Like vitamin E, 1997 was a golden year for ginkgo biloba, when a JAMA study showed that 26 weeks of ginkgo biloba boosted cognitive functioning in patients with AD more than placebo (4). Since then, studies have been quite mixed, however. An effort to replicate these findings, using a basically identical study design in 2000, failed miserably (5). And randomized controlled studies of ginkgo used by cognitively normal people have been inconsistent.

At this point, the true benefit of ginkgo is too close to call. But it's pretty darned safe, and many people swear that they think more sharply when they are on it.

TCR VERDICT:
Preventing Dementia: Lower Your Expectations

<sub>1. In't Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001; 345:1515-21.
2. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimers Disease. N Engl J Med 1997;336:1216-1222.
3. Vivekananthan DP et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-ananlysis of randomised trials. Lancet 2003;361:2017-23
4. Labars PL, et al. A placebo-controlled, double-blind, randomized trial fo an extract of ginkgo. JAMA 1997;278:1327-1332.
5. van Dongen MCJM et al.The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Geriatr Soc 2000;48:1183-1194</sub>