Omega-3 Levels in Midlife Affect Brain Structure, Cognitive Function

Omega-3 fatty acid levels in red blood cells are associated with brain structure and cognitive function in midlife.

Among middle-aged adults, higher omega-3 fatty acid concentrations were associated with superior brain structure and cognitive function, according to study findings published in Neurology.

Diet is an established predictor of body and brain health. Previous research in older adults has linked higher blood or diet omega-3 polyunsaturated fatty acids (PUFA) content with larger total brain, hippocampus, and gray matter volumes, better cognitive function, and lower risk for dementia or Alzheimer disease.

To investigate the relationship between brain health and PUFA among middle-aged adults, researchers sourced data from the third generation (n=2109) and omni two (n=74) cohorts of the Framingham Heart Study, which began enrolling participants in Massachusetts in 1948. Participants were evaluated for fatty acid levels in red blood cells, by brain magnetic resonance imaging (MRI), and neuropsychological evaluations.

The overall study population included individuals with the following characteristics:

  • mean age, 46.4±8.7 years;
  • 52.9% were women;
  • 57.4% had a college degree or above;
  • median body mass index (BMI) was 27.1 (interquartile range [IQR], 24.1-30.9) kg/m2,
  • the proportion of eicosapentaenoic acid (EPA) was 0.6% (IQR, 0.4%-0.8%),
  • docosahexaenoic acid (DHA) proportion was 4.1% (IQR, 3.4%-5.0%), and
  • omega-3 index (PUFA level) was 4.6% (IQR, 3.8%-5.8%).

Stratified by PUFA levels, participants in the lowest quartile tended to be younger, have lower educational levels, be current smokers, and fewer used lipid-lowering medications.

Further exploration indicated that APOE modulates the associations of omega-3 with brain structure and function.

In the fully adjusted models, hippocampal volume associated with EPA standard deviation units (SDU; β, 0.002; P =.038), DHA SDU (β, 0.002; P =.018), omega-3 index SDU (β, 0.003; P =.013), and the first omega-3 index quartile compared with the second through fourth quartiles (β, 0.005; P =.044).

There was also some evidence that total gray matter volume and total cortical gray matter volume associated with DHA and omega-3 index but these associations were attenuated after adjusting for BMI, blood pressure, cholesterol, smoking status, medications, and comorbidities.

The Wide Range Achievement Test (WRAT) scores associated with EPA quartiles (β, 0.48; P =.001), EPA SDU (β, 0.20; P =.003), DHA SDU (β, 0.15; P =.031), and omega-3 index SDU (β, 0.17; P =.013), and Trail Making Test A score associated with DHA quartiles (β, -0.03; P =.042).

Stratified by apolipoprotein (APOE) ε4 genotype status, among non-carriers, hippocampal volume associated with DHA SDU (β, 0.003; P =.006), DHA quartiles (β, 0.006; P =.032), omega-3 index SDU (β, 0.004; P =.005), and omega-3 index quartiles (β, 0.007; P =.013).

Whereas among carriers, white matter hyperintensities volume associated with EPA SDU (β, -0.122; P =.011), DHA SUD (β, -0.113; P =.021), and omega-3 index SDU (β, -0.120; P =.014) and WRAT scores associated with EPA SDU (β, 0.475; P =.002).

The findings of this study may not be generalizable for a more diverse population.

These data indicated that middle-aged individuals with greater blood omega-3 PUFA levels were associated with larger hippocampal volumes and better performance in abstract reasoning cognitive tests. “Further exploration indicated that APOE modulates the associations of omega-3 with brain structure and function,” the researchers added.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Satizabal CL, Himali JJ, Beiser AS, et al. Association of red blood cell omega-3 fatty acids with MRI markers and cognitive function in midlife: the Framingham Heart Study. Neurology. Published online October 5, 2022. doi:10.1212/WNL.0000000000201296