Based on the encouraging epidemiology and preclinical data, researchers have proceeded with small clinical trials to test the utility of n-3 preparations in subjects with MCI or established AD at sites in Japan, Sweden, the Netherlands, the United States, and Taiwan as listed here: 1) Japan: 240 mg/day DHA + AA (3 months) improved memory and attention in amnestic MCI patients (n = 12) but not in AD patients (n = 8).70 2) Sweden: A trial with 4 g fish oil (1.7 g DHA for 6 months; n = 174) found no significant effect in patients with a mini-mental state examination (MMSE) score of <27. In this trial, 68% of the patients were ApoE4 positive, a genotype some epidemiology suggests responds poorly. However, in a subgroup of patients with MMSE scores of >27 there was improved delayed recall and attention, and cognitive function appeared stabilized with the fish oil (n = 32).71 3) Netherlands: The Memo trial tested 302 subjects (65+ years) who were considered normal if their MMSE score was >21 (a low cutoff for “normal”). Three groups were investigated: 1,800 versus 400 mg EPA + DHA versus placebo for 26 weeks. Increases in attention were observed. Surprisingly, this was especially pronounced in the E4-positive group and in the men, but there was no change in overall cognition.72 4) Netherlands: Scheltens reported the 12-week Souvenaid trial with a proprietary nutrient mix (containing DHA, uridine monophosphate, B vitamins, and antioxidants) in 212 mild AD (MMSE scores, 20–26).73 Results showed improved delayed verbal recall, particularly in the mildest cases. Based on apparent success, a larger US-based follow-up Souvenaid trial is planned. 5) Taiwan: Chiu et al. reported the findings of a 6-month trial with MCI and AD patients in whom 1.8 g/day total n-3 appeared to result in significant improvement in Alzheimer Disease Assessment Scale-Cognitive scores compared to those in olive-oil-treated controls; however, the effect was only observed in the MCI patients, with no effect seen in the AD patients (NCT00628017).74 6) USA (Portland, Oregon): In the Oregon Health & Sciences University pilot study, in patients with MMSE scores of 15–26 (n = 39; fish oil [675 mg DHA and 975 EPA]± 600 mg ALA versus placebo), fish oil plus ALA stabilized scores for MMSE and activities of daily living (P = 0.02).75 7) USA (Martek Biosciences Corporation, Columbia, Maryland, United States): Yurko-Mauro et al. have completed MIDAS, a shorter trial in 465 subjects with pre-existing memory complaints randomized to receive 900 mg/day algal DHA for 6 months. The results, reported in July 2009 at the International Conference on Alzheimer's Disease in Vienna, show a significant improvement in the following primary outcome measures: paired associate learning, a visuospatial episodic memory test, and lowered heart rate.76
The results from these six clinical trials are not entirely consistent but generally suggest fish oil or DHA alone may have little or no benefit in cases of established AD with MMSE scores < 26 but may be useful for early intervention in subjects with mild memory complaints or minimal cognitive impairment. In addition, as reviewed elsewhere in this symposium by Dr R Wurtman, there is some evidence that, perhaps even in mild cases of established AD, a combination with other agents such as uridine monophosphate,77 B vitamins, and/or antioxidants may also be especially protective. The observation that cognitive function appeared significantly stabilized or even improved in several trials encourages additional larger trials, particularly with those at the earliest stages of decline or even for primary prevention prior to any symptoms. In the 18-month duration NIH Alzheimer's Disease Cooperative Study, DHA showed reduced cognitive decline only in non APOE4 carriers. The great advantage of nutritional or exercise intervention programs lies in their potential for primary prevention.78
Several suggested mechanisms argue for more benefits with a preventative approach. For example, because nonsteroidal anti-inflammatory drugs have generally not shown robust effects in trials for established AD but may have worked at preclinical stages in the Alzheimer's Disease Anti-Inflammatory Prevention Trial, any n-3 nonsteroidal anti-inflammatory drug-like activity in reducing AA metabolites would likely be most useful for early intervention. Similarly, the most sensitive synaptic marker index of DHA depletion in APP transgenic mouse studies was drebrin, a dendritic spine marker in excitatory synapses.30 Severe drebrin loss in hippocampus and superior temporal cortex has been reported in AD, and superior cortical drebrin loss occurs with the transition to MCI.17 Like the accumulation of Aβ1-42, which begins to plateau by the emergence of clinical decline, drebrin loss is another DHA-sensitive endpoint best suited to an early intervention.