Name: Docosahexaenoic acid (DHA)
Synonyms: Omega 3 fatty acid
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4)
Company: Martek Biosciences Corporation, NeuroBioPharm, Inc.
Docosahexaenoic acid (DHA) is one of the most abundant polyunsaturated fatty acids in the human brain. Epidemiological research has linked high DHA consumption with a lower risk of Alzheimer's disease (e.g., Morris et al., 2003). People ingest DHA from foods such as fatty fish, walnuts, or flax seeds, or from dietary supplements. These are being marketed in different formulations of DHA, or DHA mixed with other omega-3 fatty acids such as eicosapentaenoic acid (EPA). Elevated blood levels of DHA correlate with reduced dementia risk in some but not all studies (Schaefer et al., 2006; Laurin et al., 2003). Animal studies have reported a reduction of amyloid, tau, and neuritic pathology with oral intake of DHA (Lim et al., 2005; Green et al., 2007; Calon et al., 2004).
DHA has been tested in clinical trials by itself and as part of other food-supplement formulations.
In 2000, Karolinska University Hospital began the OmegAD trial, which evaluated a six-month course of treatment with a DHA-containing fish oil formulation called EPAX 1050 TG in 204 people with mild to moderate AD, of whom 174 completed the study. The treatment and placebo groups did not differ on either of the main outcome measures, decline on the MMSE and ADAS-cog, or on neurospychiatric symptoms overall. However, analysis of a small subgroup of the 32 mildest cases did suggest less decline on the MMSE, though not ADAS-cog, and a similar slowing of decline appeared to occur in the placebo group once switched to DHA after six months (Freund-Levi et al., 2006; see news and commentary, Freund-Levi 2008). Substudies suggested that DHA treatment increased CSF levels of DHA and other fatty acids and decreased levels of tau, as well as changing expression of inflammation-related genes and release of certain cytokines in white blood cells (Freund-Levi et al., 2014; Vedin et al., 2012; Vedin et al., 2008).
From 2007 to 2009, the Alzheimer's Disease Cooperative Study conducted a study at 51 centers in North America to evaluate an 18-month course of 2 grams per day of DHA in 402 patients with mild to moderate AD, of whom 295 completed the trial. DHA had no effect, relative to placebo, on rate of decline on either the ADAS-cog or the CDR-SOB clinical/functional assessement. Analysis by participants' ApoE genotype indicated a slower cognitive decline in ApoE4 non-carriers, who may have been relatively less advanced in their disease (Quinn et al., 2010, see Nov 2010 news story).
This pharmacogenetic hint of a differential effect prompted several bioavailability studies at the Universitee de Sherbrooke, Canada, between 2009 and 2011, which analyzed the percentage of DHA in lipoproteins, incorporation into plasma lipids, and pharmacokinetics by ApoE genotype in healthy young adults and people with MCI (e.g., Chouinard-Watkins et al., 2013; Plourde et al., 2014).
The largest clinical trial of DHA is the MAPT trial being conducted in four cities in France. This three-year, secondary prevention study in 1,680 patients began in 2008 and has completed enrollment of people 70 and older who report a subjective memory complaint and a mild functional loss, are frail and walk slowly, but do not meet an Alzheimer's diagnosis (Carrié et al., 2012). MAPT compares three interventions—a course of 800 mg/day of DHA alone, DHA plus a multi-domain behavioral intervention, multi-domain behavioral interventiona alone—to placebo (Gillete-Gouyonette et al., 2009). Change in memory function on the Groeber and Buschke test is the primary outcome. Results are expected in 2014.
From 2009 to 2011, the company NeuroBioPharm Inc. ran a six-month trial at 14 different sites in Canada to compare two different soft-capsule formulations of fish oil, each containing 100 mg DHA, to placebo in 175 people with mild to moderate Alzheimer's disease. This trial uses the Neuropsychological Test Battery as the primary outcome; data have not been published.
One DHA study, at Oregon Health and Science University, opened recruitment in May 2014. This trial will recruit 150 people age 80 and older who may be cognitively impaired but do not have a diagnosis of a dementing illness for a three-year course of 1.65 grams/day of EPA plus DHA compared to placebo. Seeking to understand the effect of DHA on vascular cognitive aging, this trial uses white matter hyperintensity as its primary outcome measure. Secondary and other outcome measures include other brain imaging modalities as well as blood-based indicators of endothelial health and and some neuropsychological tests. This trial is set to run until 2019.
For all clinical trials of DHA, see clinicaltrials.gov.
- First Trial of Fish Fats Shows Promise for Early AD
- Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field
- Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-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. PubMed.
- Freund-Levi Y, Basun H, Cederholm T, Faxén-Irving G, Garlind A, Grut M, Vedin I, Palmblad J, Wahlund LO, Eriksdotter-Jönhagen M. Omega-3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms. Int J Geriatr Psychiatry. 2008 Feb;23(2):161-9. PubMed.
- Freund Levi Y, Vedin I, Cederholm T, Basun H, Faxén Irving G, Eriksdotter M, Hjorth E, Schultzberg M, Vessby B, Wahlund LO, Salem N Jr, Palmblad J. Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study. J Intern Med. 2014 Apr;275(4):428-36. Epub 2014 Jan 11 PubMed.
- Vedin I, Cederholm T, Freund-Levi Y, Basun H, Garlind A, Irving GF, Eriksdotter-Jönhagen M, Wahlund LO, Dahlman I, Palmblad J. Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study. PLoS One. 2012;7(4):e35425. Epub 2012 Apr 24 PubMed.
- Vedin I, Cederholm T, Freund Levi Y, Basun H, Garlind A, Faxén Irving G, Jönhagen ME, Vessby B, Wahlund LO, Palmblad J. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008 Jun;87(6):1616-22. PubMed.
- Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR, 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. PubMed.
- Chouinard-Watkins R, Rioux-Perreault C, Fortier M, Tremblay-Mercier J, Zhang Y, Lawrence P, Vohl MC, Perron P, Lorrain D, Brenna JT, Cunnane SC, Plourde M. Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE ε4 allele. Br J Nutr. 2013 Apr 30;:1-9. PubMed.
- Plourde M, Chouinard-Watkins R, Rioux-Perreault C, Fortier M, Dang MT, Allard MJ, Tremblay-Mercier J, Zhang Y, Lawrence P, Vohl MC, Perron P, Lorrain D, Brenna JT, Cunnane SC. Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals. Am J Clin Nutr. 2014 May 14;100(1):105-112. PubMed.
- Carrié I, van Kan GA, Gillette-Guyonnet S, Andrieu S, Dartigues JF, Touchon J, Dantoine T, Rouaud O, Bonnefoy M, Robert P, Cuffi MN, Bories L, Bordes S, Gasnier Y, Desclaux F, Sudres K, Pesce A, Vellas B. Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial). J Nutr Health Aging. 2012 Apr;16(4):355-9. PubMed.
- Gillette-Guyonnet S, Andrieu S, Dantoine T, Dartigues JF, Touchon J, Vellas B, . Commentary on "A roadmap for the prevention of dementia II. Leon Thal Symposium 2008." The Multidomain Alzheimer Preventive Trial (MAPT): a new approach to the prevention of Alzheimer's disease. Alzheimers Dement. 2009 Mar;5(2):114-21. PubMed.
- Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003 Jul;60(7):940-6. PubMed.
- Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50. PubMed.
- Laurin D, Verreault R, Lindsay J, Dewailly E, Holub BJ. Omega-3 fatty acids and risk of cognitive impairment and dementia. J Alzheimers Dis. 2003 Aug;5(4):315-22. PubMed.
- Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005 Mar 23;25(12):3032-40. PubMed.
- 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. PubMed.
- Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45. PubMed.
- Hennebelle M, Plourde M, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P, Cunnane SC. Ageing and apoE change DHA homeostasis: relevance to age-related cognitive decline. Proc Nutr Soc. 2013 Oct 9;:1-7. PubMed.
- Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol. 2013 Mar;75(3):738-55. PubMed.
- Cederholm T, Salem N Jr, Palmblad J. ω-3 fatty acids in the prevention of cognitive decline in humans. Adv Nutr. 2013 Nov;4(6):672-6. Epub 2013 Nov 6 PubMed.
- Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers. Curr Alzheimer Res. 2011 Aug;8(5):470-8. PubMed.