By Makoto Ishii, MD, PhD

Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College

Dr. Ishii reports no financial relationships relevant to this field of study.

SYNOPSIS: In a randomized, placebo-controlled trial of 1,680 participants ≥ 70 years of age, there was no significant difference in cognitive decline between any of the intervention groups taking omega-3 polyunsaturated fatty acid supplementation and/or multidomain intervention (physical activity, cognitive training, and nutritional advice) compared to the placebo group. However, exploratory post hoc analyses showed some promise for a protective effect with intervention in certain at-risk subgroups.

SOURCE: Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet Neurol 2017;16:377-389.

As Alzheimer’s disease and related dementia remain incurable, there is significant interest in identifying effective prevention strategies. Previous single-domain intervention trials (e.g., nutritional supplements, cognitive training, physical activity) have found protective effects on cognitive decline, but they remain controversial because of a lack of large-scale, randomized, controlled studies. The Multidomain Alzheimer Preventive Trial (MAPT) is a pioneering large multicenter, randomized, placebo-controlled trial testing whether multidomain lifestyle intervention and polyunsaturated fatty acids, either alone or in combination, could prevent cognitive decline over 36 months.

Between 2008 and 2011, study authors enrolled 1,680 participants from 13 memory centers in France and Monaco. Participants were non-demented, ≥ 70 years of age, community dwelling, and met at least one of three criteria: spontaneous memory complaint, limitation in one instrumental activity of daily living, or slow gait speed. Exclusion criteria included Mini Mental State Examination (MMSE) < 24, any difficulty in basic activities of living, and taking polyunsaturated fatty acids supplementation at baseline. Subjects were randomly allocated (1:1:1:1) to the combined intervention with multidomain intervention plus polyunsaturated fatty acids supplementation (total daily dose of 800 mg docosahexaenoic acid [DHA] and 225 mg of eicosapentaenoic acid [EPA]), multidomain intervention plus placebo, polyunsaturated fatty acids only, or placebo only. The multidomain intervention consisted of small group sessions focused on three domains (cognitive stimulation, physical activity, and nutrition) and preventive consultation sessions with a physician to optimize cardiovascular risk factors and detect any functional impairment. The primary outcome of the study was change from baseline to 36 months in a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding Test, 10 MMSE orientation items, the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale-Revised, and the Category Naming Test). Secondary outcomes were the individual components of the composite score, scores on other cognitive tests, and scores on the Short Physical Performance Battery and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Prevention Instrument, Clinical Dementia Rating (CDR), Fried’s frailty criteria, and the Geriatric Depression Scale. One hundred fifty-four participants were excluded because of lack of follow-up cognitive assessments, and one participant withdrew consent. Adherence was lower for the multidomain intervention groups with polyunsaturated fatty acids (55%) or with placebo (53%) compared to the polyunsaturated fatty acid (79%) or placebo-alone groups (85%). In the primary efficacy analyses, there were no significant differences in three-year cognitive decline between any of the three intervention groups and placebo group. In a post hoc analysis, pooled analyses of all participants who received the multidomain intervention demonstrated significantly less cognitive decline compared to those who did not (P = 0.015), while the cognitive decline was similar between all participants who received the polyunsaturated fatty acids compared to those who did not. For secondary outcomes, the combined intervention group exhibited less of a decline in the 10 MMSE orientation items compared to the placebo group. No differences were seen in the other secondary outcome measures.

In post hoc analyses, participants in the placebo group with low baseline concentrations of DHA and EPA in red blood cells demonstrated a significant cognitive decline compared to those in the placebo group with high concentrations of DHA and EPA, whose cognitive performances remained stable, but the interventions did not alter cognitive decline in this subgroup. Additional post hoc subgroup analyses found participants with a positive amyloid PET scan receiving combined intervention or multidomain intervention plus placebo demonstrated less cognitive decline compared to those with a positive amyloid PET scan receiving placebo alone (P < 0.0001, P = 0.003, respectively).

COMMENTARY

As the first large randomized, placebo-controlled trial studying the efficacy of a lifestyle intervention with a nutraceutical compound (polyunsaturated fatty acid), MAPT is a landmark study. The negative results from the primary outcome at first may be seen as a disappointing failure for prevention intervention in dementia; however, the results from this study have yielded important information for designing future prevention trials. Results from recent Alzheimer’s disease clinical trials suggest that intervening as early as possible, such as during the pre-symptomatic or preclinical stage may be critical. In MAPT, a significant portion of the study population (~40%) had a CDR of 0.5, which may be too late for preventive intervention. Additionally, exploratory analyses found specific subgroups that exhibited decreased cognitive decline with multidomain intervention, including those individuals with positive amyloid PET scans and those with CAIDE dementia risk score of 6. Collectively, this suggests that preventive interventions may be most efficacious by targeting those with the highest risk of developing dementia as early as possible.