Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife

Abstract

Background and Objectives:Diet may be a key contributor to brain health in midlife. In particular, Omega-3 fatty acids have been related to better neurological outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) Omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults, and further explore effect modification by APOE genotype.Methods:We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate Omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs. non-carrier) on MRI and cognitive outcomes.Results:We included 2,183 dementia- and stroke-free participants (mean age 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ±0.001, p=0.04), and better abstract reasoning (0.17 ±0.07, p=0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 non-carriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all Omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers.Discussion:Our results, albeit exploratory, suggest that higher Omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-age populations are warranted to confirm these findings.

The effect of n-3 polyunsaturated fatty acid supplementation on cognitive function outcomes in the elderly depends on the baseline omega-3 index

“…14 The latest results from Framingham Heart Research showed that O3i was positively associated with hippocampal volume. 22 We observed that the baseline O3i of participants in different RCTs was obviously different, which represented different baseline n-3 nutritional statuses of the studied patients. 13,14 However, the influence of baseline O3i on different intervention outcomes seemed to be ignored before.…”

Red Blood Cell Fatty Acid Profiles Are Significantly Altered in South Australian Mild Cognitive Impairment and Alzheimer’s Disease Cases Compared to Matched Controls

“…As a future direction, it may be useful to (i) investigate whether the RBC fatty acid profiles can effectively and reliably identify those individuals who are at high risk of developing MCI to target them for primary prevention, including longitudinal studies, (ii) investigate the relationship between RBC fatty acid profiles and genotypes that may affect lipid metabolism, e.g., carriers of APOEε4 allele and polymorphisms in genes required for omega-3 and omega-6 fatty acid synthesis, such as the FADs 1 and FADs 2 genes [ 40 , 77 , 120 ] and (iii) test in intervention studies that are aimed at improving cognitive function in MCI’s which fatty acids in RBCs are best correlated with better outcomes.…”

Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimer’s Disease Mouse Model: Cellular and Molecular Correlates

“…An interaction between the stage of the disease and the ApoE genotype may explain the inconsistent results obtained with DHA supplementation. In fact, it has been suggested that APOE4 carriers showed a higher peripheral DHA catabolism that can limit DHA availability to the brain [ 9 , 44 , 45 , 46 ]. On the other hand, where long-term DHA supplementation may slow cognitive decline in an early prodromal stage of dementia, it would not affect memory decline in an advanced stage of AD [ 47 ].…”