In this cohort study, we found that lower levels of RBC DHA and EPA in late middle age were associated with markers of accelerated structural and cognitive aging. The MRI finding of lower brain volume represents a change equivalent to approximately 2 years of structural brain aging. These findings extend the observations of the Cardiovascular Health Study, which found that the consumption of fish at least 3 times a week based on dietary questionnaires was associated with a lower risk of subclinical vascular brain abnormalities.24
Fatty acids are integral components of biological membranes, and influence membrane fluidity, ion transport, and other functions.25
The neuronal cell membrane is no exception; the CNS has the highest concentration of phospholipids in the body. Long-chain omega-3 polyunsaturated fatty acids (PUFA) are abundant in the brain, particularly the omega-3 PUFA DHA and the n-6 PUFA arachidonic acid, both essential fatty acids that are very inefficiently synthesized from shorter-chain dietary precursor (α-linolenic acid and linoleic acid, respectively),26
and are best obtained preformed from the diet. Measurement of RBC fatty acid composition is a reliable biological indicator of dietary intake of omega-3 PUFAs. A longitudinal study relating RBC PUFA levels with cognitive performance showed that lower concentrations of omega-3 PUFA were associated with a higher risk of cognitive decline in an elderly French cohort followed for 4 years.27
Dietary intake of fatty fish is the main source of the omega-3 PUFAs DHA and EPA, and thus although the results of population-based studies are not all in accord, increased fish consumption has been shown by the majority of studies published to date to lower the risk of dementia and cognitive decline.28
These findings are particularly interesting when considered along with evidence that biosynthesis of EPA and DHA from their precursor α-linolenic acid appears to decrease with age.29
A recent clinical trial found that daily supplementation with DHA in older adults for 24 weeks improved learning and memory function,30
but another trial with DHA supplementation in persons with mild to moderate AD failed to show attenuation of rates of cognitive and functional decline and brain atrophy.31
In a 6-month study32
with DHA and EPA in subjects with mild to moderate AD, there was no overall delay the rate of cognitive decline, but a subanalysis in subjects with very mild AD showed a positive effect, suggesting that the protective effect of omega-3 PUFAs might occur during the earliest stages of cognitive decline.
The biological mechanisms through which omega-3 PUFAs might exert beneficial effects on the brain can be broadly divided into vascular and nonvascular pathways. DHA and EPA exert several favorable effects on the vasculature, including blood pressure reduction,33
lowering the risk of thrombosis,34
and lowering serum triglyceride levels.36
Since vascular risk factors, cerebral atherosclerosis, and stroke have been associated with a higher risk of incident dementia,37
omega-3 PUFAs may delay cognitive and structural brain aging by some combination of these mechanisms. The omega-3 PUFA composition of both lipid rafts and caveolae is known to influence membrane function and the activities of membrane-bound proteins,38
suggesting another potential mechanism of action. Other roles of omega-3 PUFAs may be more directly linked to the neurodegenerative pathogenesis of AD, including reduction of amyloid-β production, synaptic protection by reducing neuroinflammation and oxidative damage, by increasing levels of brain-derived neurotrophic factor, and through reduction of potentially excitotoxic arachidonic acid (omega-6) levels.39
Our findings of an association of RBC DHA and EPA levels with total cerebral brain volume and white matter hyperintensity volume but not with a surrogate marker of hippocampal volume, and its association with NP measures linked to vascular cognitive impairment (visual memory, executive function, abstract thinking), suggest that at least in the early preclinical phases, the underlying pathologic mechanisms may be more vascular than neurodegenerative.
The strengths of the current investigation are the focus on middle-aged to elderly subjects who were free of clinical stroke and dementia, the simultaneous availability of both structural and cognitive measures, and the use of a reliable biological measure of omega-3 fatty acid levels. Nonetheless, there are several limitations. Given that the variables used were measured during the most recent examination cycle, there were no subsequent brain MRI and NP data available to measure rates of change in both structural brain volume and cognitive performance measures. In other words, the cross-sectional design of the study precluded examination of the relationship between RBC omega-3 PUFA levels and the development of clinical dementia. In addition, the primarily Caucasian makeup of the Framingham offspring cohort may limit the generalizability of our findings to this racial/ethnic group. The association between lower RBC omega-3 fatty acid levels and markers of accelerated cognitive and structural brain aging observed here should be confirmed in other populations and extended in the future to include dementia outcomes.