New data from the third generation of the Framingham Heart Study indicate that higher red blood cell Omega-3 concentrations correlate with healthier brain structure and better cognitive function in midlife.

The study also suggests that the effects of Omega-3 fatty acids on the brain are mediated, to some degree by apolipoprotein-E (APOE) genotype.

“In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes and better abstract reasoning,” reported Claudia Satizabal, PhD, Univeristy of Texas San Antonio, the lead author of the Framingham paper which was published in the journal Neurology.

“Our results, albeit exploratory, suggest that higher Omega-3 fatty acid concentrations are related to better brain structure and cognitive function.”

Several previous epidemiological studies have shown correlations between Omega-3 levels, improved brain function, and attenuated risk of stroke or dementia. But interventional studies with Omega-3 supplements or high Omega-3 diets have given variable and inconclusive results.   

Dr. Satizabal and colleagues surmise that this is because nearly all previous studies have involved elderly subjects in whom brain changes may already be advanced and cognitive impairment is entrenched.

The new Framingham study is the first to look at the relationship between Omega-3 Index (the relative percentage of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in red blood cell membranes), and brain structure and function in middle-aged individuals.

After controlling for a range of demographic and biometric variables and potentially confounding factors, the Framingham investigators found a clear correlation between Omega-3 index readings and hippocampal volume on MRI.

The Omega-3 index more accurately reflects overall dietary intake of Omega-3 fatty acids over the prior three months than does measurement of plasma Omega-3 levels at isolated points in time.

“In the brain, DHA is incorporated into neuronal and glial cell membranes, particularly in grey matter and synapses,” the Framingham authors write. “Both DHA and EPA are metabolized into bioactive molecules involved in neurogenesis, neurotransmission, and inflammation resolution.”

A Younger Population

The new study involved 2,183 dementia- and stroke-free participants, who had a mean age 46 years.  A majority of the subjects were from the Framingham Third Generation cohort, meaning that they are grandchildren of participants in the original Framingham Heart Study which was begun in 1948. The investigators also included over 900 subjects from the Framingham Omni 1 and 2 cohorts comprised exclusively of non-white individuals.

Over half of the participants are women (53%), and 22% are carriers the APOE-e4 gene. Nearly 60% held college degrees or above.

The median Omega-3 Index reading was 4.6% (interquartile range 3.8-5.8), which Satizabal and colleagues state is “consistent with cohorts of similar age, but slightly lower than older cohorts.”

“What’s important about this study is that it replicates what we saw in the Framingham Offspring 10 years ago, in subjects who had an average age of 66. However, this study represents Generation 3, their kids essentially, who had an average of 46.”

William S. Harris, PhD, President, Fatty Acid Research Institute

All participants underwent brain MRIs, to measure total brain volume, total gray matter and hippocampal volume, as well as white matter hyperintensity volumes. They also took an array of standardized neuropsychological tests close to the times of the MRIs, to assess episodic memory, logical memory, processing speed, executive function, and abstract reasoning.

Structural & Functional Differences

After controlling for a range of demographic and biometric variables and potentially confounding factors, the Framingham investigators found a clear correlation between Omega-3 index readings and hippocampal volume on MRI.

Mean hippocampal volume was 6.9 cm³ for the participants in the top three quartiles for Omega-3 index, versus 6.8 cm³ among those in the lowest quartile.

“Every standard deviation unit increase of log-transformed Omega-3 index was related to 0.003 cm³ larger hippocampal volumes relative to intracranial volume,” Satizabal and colleagues report. The difference was statistically significant, and the general correlation also held for EPA and DHA levels independently of the composite Omega-3 index (Satizabal C, et al. Neurology. 2022).

Participants with DHA levels and Omega-3 index readings in the three upper quartiles had larger total gray and cortical gray matter volumes, as compared with those in the bottom quartile.

Notably, there was an association between higher Omega-3 index, higher DHA levels and lower white matter hyperintensity volumes. Cerebral white matter hyperintensities (WMHs) are regions of macrostructural brain damage that correlate with neurocognitive and neuromotor decline.

In addition to the structural changes, Omega-3 levels also correlated with differences in cognitive performance. Specifically, higher levels of all omega-3 parameters–EPA, DHA, and the Omega-3 index—were associated with significantly better performances on the Similarities test, a standardized assessment of abstract reasoning. This correlation remained robust after adjusting for vascular (ie, stroke) risk factors.

“Every standard deviation unit increase of log-transformed Omega-3 index was related to 0.003 cm³ larger hippocampal volumes relative to intracranial volume,”

Claudia Satizabal, PhD, University of Texas, San Antonio

Impact of APOE

The Framingham researchers found that APOE-e4 status had some effect on the relationship between Omega-3 levels and indicators of brain health.

For example, the positive relationship between higher DHA levels and increased hippocampal volume was only present in participants who were non-carriers of the APOE-e4 allele. It was not seen in carriers of the gene.

On the other hand, the reduction in WMH seen in connection with higher EPA, DHA, and Omega-3 index levels, was only found in the APOE-e4 carriers. Carriers also showed a relationship between increasing EPA levels and better performance on the Similarities test. This was not seen in the non-carriers.

“Stratification by APOE status in our study suggested distinct potentially protective associations of omega-3 PUFA with gray and white matter.” The clinical significance of these APOE-related effects is not entirely clear. But given that APOE has a role in the transport and metabolism of lipids, and is involved in the movement of omega-3 fatty acids into the brain, it makes sense that gene-based variations in APOE would influence the relationship between circulating Omega-3 levels and brain function.

The Framingham authors note that their findings are in line with population studies suggesting differential effects by APOE status in the association between omega-3 PUFA and neurocognitive indicators.

“It has been suggested that APOE-e4 carriers have different patterns of brain activity at younger ages, including larger white matter volumes, better white matter integrity on DTI (diffusion tensor MRI), as well as better attention. Alternatively, the beneficial effects of omega-3 PUFA on brain white matter may occur through other pathways related to reductions of vascular risk factors that may contribute to cerebral small vessel disease.”

Satizabal and colleagues believe APOE status is an important consideration for future studies of the impact of Omega-3s on brain health. It is a factor that has usually been overlooked in past studies, and it could account for some of the discrepancies between observational studies showing robust correlations between Omega-3s and brain health, and interventional studies giving equivocal outcomes.

Start Early

Past interventional studies may also be hindered by the fact that most of them tested diet or supplement interventions in elderly people who already have significant cognitive impairment. In other words, the interventions are started too late in the course of the disease.

“Epidemiological and intervention studies suggest omega-3 PUFA may be most beneficial to preserve brain health from early midlife, as our study suggests, and just before the onset of moderate cognitive changes.”

“What’s important about this study is that it replicates what we saw in the Framingham Offspring 10 years ago, in subjects who had an average age of 66. However, this study represents Generation 3, their kids essentially, who had an average of 46,” explained William S. Harris, PhD, one of the authors of the current study. Harris is also president of the Fatty Acid Research Institute (FARI), and co-inventor of the Omega-3 Index testing method.

“The results of this study show that low red blood cell DHA levels are associated with smaller brain volumes and a ‘vascular’ pattern of cognitive impairment, even in persons free of clinical dementia,” said Harris in a press release following publication of the Satizabal study.

“This suggests that intervening early and maintaining an optimal Omega-3 Index (8% or higher) could play an important role in staving off cognitive decline, as well as dementia and Alzheimer’s in the long-term,” Dr. Harris said.

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