Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial.

JAMA

Nov 2010

DOI: 10.1001/jama.2010.1510

Citations:766

Influential Citations:37

Interventional (Human) Studies

Enhanced Details

Methods

Randomized, double-blind, placebo-controlled trial across 51 US centers; participants with probable Alzheimer's disease; MMSE 14–26; medically stable; not taking DHA or omega-3 supplements; allowed cholinesterase inhibitors or memantine; 402 randomized (238 DHA, 164 placebo) over 18 months.

Intervention

Algal-derived DHA capsules, total daily dose 2 g (1 g capsule taken twice daily) for 18 months.

Results

DHA supplementation did not slow cognitive or functional decline over 18 months in mild-to-moderate Alzheimer's disease. Primary outcomes showed no significant between-group differences: ADAS-cog change rate—placebo 8.27 vs DHA 7.98 (P=0.41); CDR sum of boxes—placebo 2.93 vs DHA 2.87 (P=0.68). Secondary outcomes (ADCS-ADL, NPI) also showed no benefit; MRI markers showed no DHA-related brain volume changes. An exploratory analysis suggested potential benefit in APOE ε4-negative participants for ADAS-cog and MMSE, but findings were not consistent across outcomes and not adjusted for multiple comparisons. Conclusion: DHA supplementation is not useful for slowing progression in mild-to-moderate Alzheimer disease and is not recommended for this population. Dropout rates were similar (DHA 28%, placebo 24%).

Limitations

High 18-month dropout rate (DHA 28%, placebo 24%); MRI substudy was a convenience sample and not randomly selected; exploratory APOE ε4 findings require replication and multiple-comparison adjustment; results apply to mild-to-moderate Alzheimer's disease and may not generalize to earlier stages or prevention contexts.

Abstract

CONTEXT Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. OBJECTIVE To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study. INTERVENTION Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. MAIN OUTCOME MEASURES Change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). RESULTS A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). CONCLUSION Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00440050. show less