Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging

Abstract

Objective: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middleaged to elderly community-based cohort. Methods:We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n ϭ 1,575; 854 women, age 67 Ϯ 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ⑀4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). Results:Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: ␤ Ϯ SE ϭ Ϫ0.49 Ϯ 0.19; p ϭ 0.009, and 0.12 Ϯ 0.06; p ϭ 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and -3 index (RBC DHAϩEPA) levels (Q1 vs Q2-4) also had lower scores on tests of visual memory (␤ Ϯ SE ϭ Ϫ0.47 Ϯ 0.18; p ϭ 0.008), executive function (␤ Ϯ SE ϭ Ϫ0.07 Ϯ 0.03; p ϭ 0.004), and abstract thinking (␤ Ϯ SE ϭ Ϫ0.52 Ϯ 0.18; p ϭ 0.004) in model A, the results remaining significant in all models. Conclusion:Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia. Neurology ® 2012;78:658-664 GLOSSARY AD ϭ Alzheimer disease; BMI ϭ body mass index; DHA ϭ docosahexaenoic acid; DM ϭ diabetes mellitus; EPA ϭ eicosapentaenoic acid; LM-d ϭ delayed recall components of the Logical Memory test; NP ϭ neuropsychological; PAI ϭ physical activity index; PUFA ϭ polyunsaturated fatty acid; RBC ϭ red blood cell; SBP ϭ systolic blood pressure; SCI ϭ silent cerebral infarct; SIM ϭ Similarities test; TCBV ϭ total cerebral brain volume; THV ϭ temporal horn volume; VR-d ϭ delayed recall component of the Visual Reproductions test; WMHV ϭ white matter hyperintensity volume.Higher fish intake has been associated with a reduced risk of cardiovascular mortality 1,2 and stroke.3 While several large epidemiologic studies 4,5 have shown an association between the estimated intake of fatty fish and a lower risk for dementia, some other investigations have failed to confirm such a protective association. 6 One possible reason for these inconsistent results is the limited ability of dietary recall surveys and food frequency questionnaires to quantify blood levels of fatty acids. 7,8 In the Framingham original cohort, participants in the top quartile of plasma phosphatidylcholine docosahexaenoic acid (DHA) levels had 37% and 47% lower risks of Alzheimer disease (AD) and all-cause dementia, respectively.9 Red blood ...

Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial

“…PNPLA3 (I148M) GG was associated with decreased DHA enrichment but was not associated with EPA enrichment. It is known that omega-3 fatty acids are rapidly incorporated into plasma membranes where they affect membrane fluidity and membrane permeability (36) and that measurement of erythrocyte DHA and EPA enrichment is considered a good proxy for omega-3 fatty acid enrichment and bioavailability in liver (37). However, based on our results, PNPLA3 I148M is involved in DHA/EPA mobilization in liver and subjects with PNPLA3 (I148M) GG genotype have lower levels of DHA (38).…”

Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes

“…Similarly, in the Framingham Offspring cohort (n 5 1,575, 54% women, average age 67 years), participants with an omega-3 index in the first quartile had a smaller average brain volume (20.49%) compared with those in the upper 3 quartiles, which was described as being equivalent to approximately 2 years of normal brain aging. 13 In our multicenter, women-only study, we found no relations between ischemic lesion volumes (which represented both diffuse small-vessel disease and the hyperintensities that surround focal lesions) and marine omega-3 FAs. This is in contrast to the Framingham study, which reported greater white matter hyperintensity volumes as a percentage of intracranial volume with lower DHA levels.…”

“…This is in contrast to the Framingham study, which reported greater white matter hyperintensity volumes as a percentage of intracranial volume with lower DHA levels. 13 A plasma nutrient biomarker pattern that included EPA, DHA, and 12 other nutrients was also inversely related to white matter hyperintensity volumes. e1 The Cardiovascular Health Study (n 5 2,465, 59% women, average age 75 years) reported less likelihood of subclinical infarcts, defined as ischemic lesions $3 mm in diameter, for participants who ate fatty, nonfried fish more frequently.…”

“…12 Most relevant to the present study, total brain volumes were directly related to RBC omega-3 levels in the Framingham Offspring cohort. 13 In our study, we hypothesized that marine omega-3 FAs would be directly related to total brain volumes determined by MRI 8 years later, and then explored the relations in ischemic tissue and 13 gray and white matter anatomical regions.…”

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

“…AD and MCI patients exhibit lower levels of long-chain polyunsaturated fatty acids (PUFA) of Omega-3 series in RBC membranes compared with healthy controls [77]. Moreover, lower erythrocytes levels of Omega-3 PUFA, eicosapentaenoic acid and docosahexaenoic acid, were shown to be associated with smaller brain volumes and a 'vascular' pattern of cognitive impairment [78]. The findings in AD erythrocytes support the erythrocytic/vascular hypothesis of AD and contribute to a molecular signature of AD in RBCs.…”