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

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.

Figure 1

Flow of Patients in the Alzheimer’s Disease Cooperative Study (ADCS) Docosahexaenoic Acid Supplementation Trial Study partner issue is included as a reason for discontinuation because of the requirement for a study partner to participate in several of the key outcome measures in this trial (eg, Clinical Dementia Rating sum of boxes, ADCS activities of daily living, and Neuropsychiatric Inventory). There were no significant differences in incidence of dropout, adverse events, or serious adverse events (Table 2). ^aThere could be more than 1 reason for exclusion or study discontinuation.

Figure 2

Change in Primary and Secondary Outcome Measures in the Alzheimer’s Disease Cooperative Study (ADCS) Docosahexaenoic Acid (DHA) Supplementation Trial All randomized participants were included in these intention-to-treat analyses. Error bars indicate 95% confidence intervals. There was no effect of DHA on rate of cognitive change on the Alzheimer’s Disease Assessment Scale (ADAS; linear mixed-effects model: P = .41), Clinical Dementia Rating (CDR) sum of boxes (linear mixed-effects model: P = .68), ADCS activities of daily living scale (linear mixed-effects model: P = .38), or Neuropsychiatric Inventory (NPI; linear mixed-effects model: P = .11). Scores for the ADAS-cog and CDR sum of boxes were the prespecified primary outcome measures; others were secondary outcomes.

Figure 3

Rate of Cognitive Change on Alzheimer’s Disease Assessment Scale (ADAS) Divided by Apolipoprotein E (APOE) Genotype Error bars indicate 95% confidence intervals. The linear mixed-effects analysis finds no effect of docosahexaenoic acid (DHA) on the rate of ADAS-cog change in APOE ε4–positive participants but when the analysis is confined to APOE ε4-negative participants, the rate of change in ADAS-cog is slower in participants treated with DHA than in participants treated with placebo (linear mixed-effects model: P = .03). There was no evidence of a DHA effect on Clinical Dementia Rating sum of boxes, Alzheimer’s Disease Cooperative Study activities of daily living, or Neuropsychiatric Inventory on rates of brain atrophy (see “Results” section).