Name:	Docosahexanoic acid (DHA)
Other Names:	Omega 3 fatty acids
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Nutraceutical
Mechanisms:	DHA is a major component of neuron membranes and has multiple functions, including modulation of presenilin.
Development Status:	investigational in U.S.
FDA Phase:	Phase III
Primary Medical Role:	Docosahexanoic acid (DHA) is an omega n-3 polyunsaturated fatty acid found in fish and some marine algae, and is available as a nutraceutical dietary supplement. Sixty percent of the fatty acids that make up neuronal cell membranes of the retina consist of DHA, and it is found particularly concentrated in synaptic membranes (Bazan and Scott, 1990). DHA is essential for prenatal brain development and for healthy postnatal brain function. Infants fed vegetable oil-based formulas tend to have poorer visual function, lower cognitive scores, and acquire learning tasks more slowly than infants who were breast fed or fed DHA-supplemented formula (Moriguchi and Salem, 2003). Newborn rats fed with diets deficient in DHA demonstrate a deficit in spatial task performance, poorer memory retention in the Morris water maze compared with n- 3 fatty acid adequate and dam-reared rats (Lim et al., 2005), as well as poorer 2-odor olfactory discrimination acquisition and deficits in olfactory-based reversal learning tasks (Greiner et al., 1999).
Role in Alzheimer's Disease:	Alzheimer disease patients have significantly lower DHA levels compared to control subjects, and serum cholesteryl ester-DHA levels are progressively reduced with severity of clinical dementia (Tully et al., 2003). A previous omega-3 fatty acid treatment (a mixture of DHA and EPA) clinical trial in Sweden demonstrated a significant (P <.05) reduction in MMSE decline rate in the omega-3 fatty acid-treated group compared with the placebo group in a subgroup of patients with a very mild cognitive dysfunction, observed at 6 and 12 months (Freund-Levi et al., 2006). Two Phase III clinical trials of purified DHA from microalgae have been performed in the US. The MIDAS study was a 6 month study in 485 healthy older adults with age-related cognitive decline (not MCI or AD). No ApoE genotyping was done in this study. Statistically significant improvements with 900mg/d algal DHA were observed over placebo on the PAL test with nearly double the reduction in errors on the test in the DHA group compared to placebo, demonstrating improvements in learning and episodic memory function over 6 months in these subjects (Yurko-Mauro et al 2009). An 18-month study in mild to moderate AD patients did not meet its primary endpoints, but a secondary analysis of data by ApoE4 genotype showed significant effects on the ADAS-Cog with DHA in patients without the ApoE4 gene. Significant results were also seen on MMSE scores at 18mths versus baseline in this group (Quinn et al 2009). Results from phase III clinical trial NCT00440050 showed that administration of daily DHA for 18 months did not slow cognitive or functional decline in AD patients (Quinn et al 2010).
Pharmacological Role:	DHA is a major component of brain synaptic plasma membranes and has multiple roles in the brain. First, lipid-bound DHA in the membrane bilayer confers a high degree of flexibility and direct interaction with membrane proteins, thus affecting speed of signal transduction (Grossfield et al., 2006), both serotonergic and dopaminergic neurotransmission (Chalon, 2006), and formation of lipid rafts (Stillwell et al., 2005). Secondly, unesterified DHA appears to have roles in regulating gene expression (Kitajka et al., 2002), ion channel activities (Vreugdenhil et al., 1996), and is further metabolized to form neuroprotectin D1, which inhibits oxidative stress-mediated proinflammatory gene induction and apoptosis in the brain (Bazan, 2006). DHA is important in neurogenesis (Coti Bertrand et al., 2006; Kawakita et al., 2006) and induces changes in cellular phosphatidylserine (Salem et al., 2001). DHA supplementation in mouse chow can reduce amyloid pathology in Tg2576 mice (Lim et al., 2005), and a recent report (Green et al., 2007) has now shown that DHA reduces steady- state levels of PS1 mRNA and protein levels as compared to control.
Side Effects:	DHA is well tolerated and occurs naturally in microalgae and fish oils. In the Freund-Levi et al., 2006 trial, the DHA+EPA omega-3 fatty acid preparation was shown to be well tolerated and safe. The dropout rate was approximately 15 percent in the treatment arm, similar to 14 percent in the placebo group. Gastrointestinal tract symptoms such as diarrhea, dysphagia (problems in swallowing due to the size of the capsules), somatic disease, and noncompliance were listed as reasons for leaving the study. A comparable breakdown in the placebo dropout group was not provided. No significant changes in routine blood or urine chemistry were noted between the two groups. Blood pressure remained unchanged. Both Martek trials with purified DHA from microalgae, showed similar tolerability and safety profiles, with no treatment-related adverse effects reported.
Evidence pro its efficacy:	The Freund-Levi et al., 2006 study demonstrated a significant (P <.05) reduction in MMSE decline rate observed in the DHA+EPA treated group compared with the placebo group in patients with very mild cognitive dysfunction, but not in patients with moderate AD. The 6-month Martek study in healthy older adults showed significan improvement in the PAL memory test (Yurko-Mauro et al 2009). The 18 month ADCS-Martek study showed significant effects on both ADAS-cog and MMSE in DHA-treated, mild to moderate AD patients without the ApoE4 allele, compared to baseline, at the final 18 months timepoint (Quinn et al, 2009).
Evidence con its efficacy:	The Freund-Levi et al., 2006 clinical study with DHA+EPA did not find statistically significant changes in MMSE, ADAS- Cog, or CDR scores in comparison of total treatment vs. total placebo groups. This is consistent with a lack of efficacy seen in a shorter (12-week) trial in the U.K. testing ethyl-EPA in Alzheimer disease (Boston et al., 2004).
Companies:	Martek Biosciences Corporation
Notes:	This record updated November 18, 2010.

References

Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR Jr, Weiner M, Shinto L, Aisen PS. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010 Nov 3;304(17):1903-11. POW Link

Joseph F. Quinn, Rema Raman, Ronald G. Thomas, Karin Ernstrom, Karin Yurko-Mauro, Edward B. Nelson, Lynne Shinto, Anil K. Nair, Paul Aisen. 2009. A clinical trial of docosahexanoic acid (DHA) for the treatment of Alzheimer's disease. Alzheimer's & Dementia. July 2009 Vol. 5, Issue 4, Page P84 Abstract

Yurko-Mauro K, McCarthy D, Bailey-Hall E, Nelson EB, Blackwell A. 2009. Results of the MIDAS trial: Effects of docosahexaenoic acid on physiological and safety parameters in age-related cognitive decline. Alzheimer's & Dementia July 2009 Vol. 5, Issue 4, Page P84 Abstract

Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko- Mauro KA, Ellis L, LaFerla FM. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci. 2007 Apr 18;27(16):4385-95. Abstract

Chalon S. Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):259-69. Abstract

Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. Abstract

Coti Bertrand P, O'Kusky J, Innis SM. Maternal dietary n-3 fatty acid deficiency alters neurogenesis in the embryonic rat brain. J Nutr. 2006 Jun;136(6):1570-5. Abstract

Bazan NG. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci. 2006 May;29:263–71. Abstract

Grossfield A, Feller SE, Pitman MC. A role for direct interactions in the modulation of rhodopsin by omega-3 polyunsaturated lipids. Proc Natl Acad Sci USA. 2006 Mar 28;103(13):4888-93. Abstract

Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience. 2006;139:991–7. Abstract

Lim SY, Hoshiba J, Moriguchi T, Salem N Jr. N-3 fatty acid deficiency induced by a modified artificial rearing method leads to poorer performance in spatial learning tasks. Pediatr Res. 2005 Oct;58(4):741-8. Abstract

Stillwell W, Shaikh SR, Zerouga M, Siddiqui R, Wassall SR. Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reprod Nutr Dev. 2005 Sep-Oct;45(5):559-79. Abstract

Boston PF, Bennett A, Horrobin DF, Bennett CN. Ethyl-EPA in Alzheimer’s disease: a pilot study. Prostaglandins Leukot Essent Fatty Acids. 2004 Nov;71:341-346. Abstract

Moriguchi T, Salem N Jr. Recovery of brain docosahexaenoate leads to recovery of spatial task performance. J Neurochem. 2003 Oct;87(2):297-309. Abstract

Tully AM, Roche HM, Doyle R, Fallon C, Bruce I, Lawlor B, Coakley D, Gibney MJ. Low serum cholesteryl ester- docosahexaenoic acid levels in Alzheimer's disease: a case- control study. Br J Nutr. 2003 Apr;89(4):483-9. Abstract

Kitajka K, Puskas LG, Zvara A, Hackler L, Jr., Barcelo- Coblijn G, Farkas ST. The role of n-3 fatty polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA. 2002 Mar 5;99(5):2619-24. Abstract

Salem N, Jr., Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic aicd in the nervous system. Lipids. 2001 Sep;36:945–59. Abstract

Greiner RS, Moriguchi T, Hutton A, Slotnick BM, Salem N Jr. Rats with low levels of brain docosahexaenoic acid show impaired performance in olfactory-based and spatial learning tasks. Lipids. 1999;34 Suppl:S239-43. Abstract

Vreugdenhil M, Bruehl C, Voskuyl RA, Kang JX, Leaf A, Wadman WJ. Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci USA. 1996 Oct 29;93(22):12559-63. Abstract

Bazan NG, Scott BL. Dietary omega-3 fatty acids and accumulation of docosahexaenoic acid in rod photoreceptor cells of the retina and at synapses. Ups J Med Sci Suppl. 1990;48:97-107. Abstract