The apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer’s disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes.
Using positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19–65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed.
The mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups.
Our findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk.
Weisgraber KH, Innerarity TL, Mahley RW. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem. 1982;257(5):2518–21. PubMed
La L, Hansen HS, Jørgensen MH, Michaelsen KF. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res. 2001;40(1):1–94.
Hjorth E, Zhu M, Toro VC, Vedin I, Palmblad J, Cederholm T, et al. Omega-3 fatty acids enhance phagocytosis of Alzheimer’s disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J Alzheimers Dis. 2013;35(4):697–713. PubMed
Hooijmans CR, Rutters F, Dederen PJ, Gambarota G, Veltien A, van Groen T, et al. Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD). Neurobiol Dis. 2007;28(1):16–29. CrossRefPubMed
Lands WEM, Crawford CG. Enzymes of membrane phospholipid metabolism in animals. In: Martonosoi A, editor. The enzymes of biological membranes, Biosynthesis of cell components, vol. 2. New York: Springer; 1976. p. 3–85.
Umhau JC, Zhou W, Thada S, Demar J, Hussein N, Bhattacharjee AK, et al. Brain docosahexaenoic acid [DHA] incorporation and blood flow are increased in chronic alcoholics: a positron emission tomography study corrected for cerebral atrophy. PLoS One. 2013;8(10):e75333. Pubmed Central PMCID: 3788756. CrossRefPubMedPubMedCentral
Cheon Y, Kim HW, Igarashi M, Modi HR, Chang L, Ma K, et al. Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A 2-VIA (iPLA 2β)-knockout mice. Biochim Biophys Acta. 2012;1821(9):1278–86. Pubmed Central PMCID: PMC3393806. CrossRefPubMedPubMedCentral
Giovacchini G, Lerner A, Toczek MT, Fraser C, Ma K, DeMar JC, et al. Brain incorporation of 11C-arachidonic acid, blood volume, and blood flow in healthy aging: a study with partial-volume correction. J Nucl Med. 2004;45(9):1471–9. PubMed
- DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA
Hussein N. Yassine
Joseph R. Hibbeln
Stanley I. Rapoport
Stephen C. Cunnane
John C. Umhau
- BioMed Central