Very recent findings confirmed that S-adenosylmethionine (SAM) can exert a direct effect on glutathione S-transferase (GST) activity. Alzheimer's disease (AD) is accompanied by reduced GST activity, diminished SAM, and increased S-adenosyl homocysteine (SAH), the downstream metabolic product resulting from SAM-mediated transmethylation reactions, when deprived of folate. Therefore, these findings underscored the critical role of SAM in maintenance of neuronal health, suggesting a possible role of SAM as a neuroprotective dietary supplement in AD. Given recent findings from clinical trials in which omega-3 polyunsturated fatty acids (PUFA) supplementation was effective only in very mild AD subgroups or mild cognitive impairment (MCI), we suggest intervention trials using measures of dietary supplementation (dietary omega-3 PUFA and SAM plus B vitamin supplementation) to determine if such supplements will reduce the risk for cognitive decline in very mild AD and MCI. Therefore, key supplements are not necessarily working in isolation, and the most profound impact, or in some cases the only impact, is noted very early in the course of AD, suggesting that nutriceutical supplements may bolster pharmacological approaches well past the window where supplements can work on their own.