Science

Claudia L. Satizabal, Jayandra Jung Himali, Alexa S. Beiser, Vasan Ramachandran, Debora Melo van Lent, Dibya Himali, Hugo J. Aparicio, Pauline Maillard, Charles S. DeCarli, William Harris, Sudha Seshadri

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.