Research Article: Docosahexaenoic Acid and Adult Memory: A Systematic Review and Meta-Analysis

Date Published: March 18, 2015

Publisher: Public Library of Science

Author(s): Karin Yurko-Mauro, Dominik D. Alexander, Mary E. Van Elswyk, Hemachandra Reddy.


Subjective memory complaints are common with aging. Docosahexaenoic acid (DHA; 22:6 n-3) is a long-chain polyunsaturated fatty acid (LCPUFA) and an integral part of neural membrane phospholipids that impacts brain structure and function. Past research demonstrates a positive association between DHA plasma status/dietary intake and cognitive function.

The current meta-analysis was designed to determine the effect of DHA intake, alone or combined with eicosapentaenoic acid (EPA; 20:5 n-3), on specific memory domains: episodic, working, and semantic in healthy adults aged 18 years and older. A secondary objective was to systematically review/summarize the related observational epidemiologic literature.

A systematic literature search of clinical trials and observational studies that examined the relationship between n-3 LCPUFA on memory outcomes in healthy adults was conducted in Ovid MEDLINE and EMBASE databases. Studies of subjects free of neurologic disease at baseline, with or without mild memory complaints (MMC), were included. Random effects meta-analyses were conducted to generate weighted group mean differences, standardized weighted group mean differences (Hedge’s g), z-scores, and p-values for heterogeneity comparing DHA/EPA to a placebo. A priori sub-group analyses were conducted to evaluate the effect of age at enrollment, dose level, and memory type tested.

Episodic memory outcomes of adults with MMC were significantly (P<.004) improved with DHA/EPA supplementation. Regardless of cognitive status at baseline, > 1 g/day DHA/EPA improved episodic memory (P<.04). Semantic and working memory changes from baseline were significant with DHA but no between group differences were detected. Observational studies support a beneficial association between intake/blood levels of DHA/EPA and memory function in older adults. DHA, alone or combined with EPA, contributes to improved memory function in older adults with mild memory complaints.

Partial Text

Docosahexaenoic acid (DHA; 22:6 n-3), is a long-chain omega-3 fatty acid (n-3 LCPUFA) and is an integral part of neural membrane phospholipids and as such impacts brain structure and function. Early in life DHA is rapidly accumulated by neural tissue contributing to development of the brain and eyes [1]. At the opposite of end of the age spectrum many, but not all, observational studies demonstrate a beneficial association between DHA and /or EPA blood levels/dietary intake and various aspects of cognitive function in older adults [2,3,4]. Results from clinical trials evaluating the effect of DHA on cognitive function are difficult to summarize however, due, at least in part, to the myriad of cognitive tests employed between studies and the diversity of subjects with regard to age and cognitive status. To date, meta-analyses of clinical trials have assessed composite memory scores or the results of individual memory tests, e.g. immediate recall, as opposed to a particular memory domain, and have considered data almost exclusively from trials of older adults [5,6,7,8]. A recent meta-analysis of composite memory scores reported in clinical trials supplementing DHA, alone or in combination with EPA (DHA/EPA), to older adults found no benefit on composite memory, but reported a significant improvement in immediate recall among individuals with mild memory complaints (MMC) [8]. Immediate recall specifically tests episodic memory [9]. Among cognitive deficits, subjective memory complaints are common in the aging population with changes in episodic memory being some of the earliest cognitive changes observed in older adults [10,11,12]. In an effort to more clearly define the role that DHA/EPA supplementation may play in specific aspects of memory function and to better understand responsiveness to DHA/EPA supplementation with aging, the current meta-analysis uniquely categorized results of memory tests from clinical trials into individual memory types, i.e. episodic, semantic, and working memory, and included results from trials of healthy adults (18 years and older) with or without MMC. The current meta-analysis was designed to determine the effect of supplementation of DHA alone, or in combination with EPA, on specific memory functions in healthy adults participating in clinical trials. A secondary objective was to systematically review the observational epidemiologic literature on DHA/EPA and memory outcomes to date in healthy adults.

Memory is divided into two general types, declarative and non-declarative. Declarative memory relates to the conscious recollection of facts and events and can be further sub-divided into episodic and semantic [43]. Episodic memory is memory for personally experienced events that occur at a specific place and time and is measured by memory of stories, word lists, or figures [43]. Episodic memory typically declines throughout life and is consistent with normal, healthy aging decline [43]. Aging adults are concerned with memory loss, even more so than with cardiovascular health or physical activity [44]. The current meta-analysis results with DHA suggest a benefit of supplementation in improving episodic memory function in healthy adults with MMC and are consistent with those of Mazereeuw and co-workers [8] for improvements in the immediate recall sub-category of episodic memory. The strength and uniqueness of the current meta-analysis approach is that it allows demonstration of DHA/EPA improvements across a variety of individual memory tests within the category of episodic memory not otherwise noticeable in a composite of memory outcomes. The studies included in this meta-analysis varied in sample size and demographics (e.g. age, gender, education) as well as duration of supplementation, yet the effect of DHA/EPA supplementation across these studies was significant. Examining the data in this manner also allowed for the observation of additional relationships, in particular, the role of DHA/EPA dose in memory improvement. While Mazereeuw et al. [8] did not find an association of dose on the treatment effect size for a single test of episodic memory, i.e. immediate recall, the current analysis found that multiple tests for episodic memory, regardless of cognitive status (MMC and NCC combined, n = 19 data points), demonstrated an improvement in performance from at least 1 g/d of DHA+EPA. Data showed that this benefit is apparently driven by DHA, in particular, at a level between 501–999 mg/day. Data were likely insufficient to evaluate doses of DHA >1 g, as only 9 data points were available from studies providing this dose range. Discrepancies between our meta-analysis findings and 2 recent meta-analyses are likely due to differences in designs and criteria for combining studies on n-3 LCPUFA and cognition. Jiao and co-workers [45] examined studies across wide age ranges, i.e. infancy to elderly and did not provide appropriate sub-group analyses by age or dose. This approach is problematic as cognitive assessment is dependent upon brain development milestones in the young and is not pertinent to older adults, and use of such wide doses within a single analysis makes meaningful interpretation of results difficult. The meta-analysis by Abubakari and co-workers [7] combined studies of healthy adults with disease populations (e.g. AD, depression, schizophrenia) and thus included a large array of cognitive tests. Heterogeneity of baseline cognitive function across these populations and varied sensitivity of assessments may have obscured important between group differences for DHA/EPA supplementation versus placebo.

DHA supplementation, alone or in combination with EPA, is associated with improved episodic memory in adults with mild memory complaints. The meta-analytic results demonstrate a significant impact on age-associated memory loss which is a major health concern of older adults. Additional long-term intervention studies examining the role that DHA/EPA may play in semantic and working memory outcomes in aging individuals are needed. Observational data support a broad role of DHA/EPA intake and its positive effects on memory and cognition in older adults.