Therapeutics

Docosahexaenoic acid (DHA)

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Overview

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.

Background

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, Zhang et al., 2016). 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).

In early epidemiology work, elevated blood DHA levels correlated with reduced dementia risk in some but not all studies (Schaefer et al., 2006; Laurin et al., 2003). Newer studies support the link between DHA intake or blood levels and a reduced risk of cognitive decline or AD (e.g. Wei et al., 2023; He et al., 2023; Shang et al., 2018). In people with AD, higher serum DHA was associated with slower cognitive decline (Chu et al., 2022). An analysis of ADNI data associated low omega-3 in red blood cells with greater Aβ accumulation and memory decline (Rouch et al., 2022). Data from the large Framingham Heart study correlated higher DHA or EPA in red blood cells with larger hippocampal volume and better abstract reasoning at midlife, and up to half the risk of incident AD in older adults (Satizabal et al., 2022; Sala-Vila et al., 2022). This and other studies (e.g., Sala-Vila et al., 2021; Coughlan et al., 2021) indicate that ApoE4 genotype affects the relationship of DHA status to cognition and neurodegeneration biomarkers (for review see Zhange et al., 2023). More recently, a cross-sectional analysis correlated higher blood omega-3 concentrations with better brain glucose uptake in participants at risk of AD (Lazaro et al., 2024).

In contrast, U.K. Biobank data indicate fish oil supplementation in older people reduced risk of all-cause dementia, but not specifically of AD (Huang et al., 2022; Liu et al., 2022). In the same population, total omega-3 status, but not DHA alone, correlated with lowered risk of dementia (Sala-Vila et al., 2023). A smaller study found no association of circulating DHA with incident dementia over 13 years (de Oliveira Otto et al., 2023).

Multiple autopsy studies have described deficits of DHA-containing phospholipids in brain tissue from people with Alzheimer's, which correlates with markers of the disease (reviewed in Heath and Wood, 2021). In samples from dementia with Lewy body cases, low levels of DHA-containing phospholipids were associated with lower soluble Aβ42, higher phosphorylated α-synuclein, and diminished synaptic proteins (Chong et al., 2023).

In animal studies, oral intake of DHA leads to a reduction of amyloid, tau, and neuritic pathology (Lim et al., 2005; Green et al., 2007; Calon et al., 2004). This appears to stem from beneficial effects on amyloid processing, inflammation, oxidative stress, and metabolic function (for review see Mett 2021). In APP/PS mice, omega-3 supplementation reversed some effects of a high-fat diet on Aβ peptide expression, insulin resistance, and inflammation (Ma et al., 2022). DHA reduced retinal amyloid pathology in 5XFAD mice, when delivered as a lysophosphatidylcholine form uniquely bioavailable to retinal cells (Sugasini et al., 2023). Nasal delivery of DHA reduced tau phosphorylation and improved cognitive function in J20 transgenic mice, or after brain injection of Aβ peptides in normal mice (Zussy et al., 2022). DHA supplementation also reversed cognitive and olfactory deficits due to ApoE4 expression in transgenic mice (González et al., 2023; Lessard-Beaudoin et al., 2021).

Findings

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 neuropsychiatric symptoms overall. However, analysis of a small subgroup of the 32 mildest cases did suggest less decline on the MMSE, though not ADAS-Cog; 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 et al., 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 and inflammatory mediators in white blood cells (Freund-Levi et al., 2014; Vedin et al., 2012; Vedin et al., 2010; Vedin et al., 2008; Wang et al., 2015). Other substudies reported no effect on CSF biomarkers of inflammation or amyloidosis, or urine biomarkers of oxidative stress (Freund-Levi et al., 2009; Freund-Levi et al., 2014). Supplementation appeared to increase plasma, but not CSF transthyretin, a cofactor for Aβ clearance (Faxen-Irving et al., 2013). The treatment caused a global DNA hypomethylation measured in blood cells, but the effect correlated more strongly with EPA blood concentrations than DHA (Karimi et al., 2017).

Additional post hoc analyses of this trial showed a dose response between the increase in omega-3 plasma levels after supplementation, and slowing of decline on the ADAS-Cog (Eriksdottir et al., 2015). Patients with better Vitamin B status showed more improvement after supplementation on the MMSE and CDR-SB, but not the global CDR or ADAS-Cog (Jerneren et al., 2019). Most recently, analysis of a panel of CSF biomarkers revealed an increase in YKL-40 and NfL after six months of supplementation, while other markers of Aβ, tau, and inflammation were stable (Tofiq et al., 2021).

A Dutch study conducted in 2006 reported no effect of six months of fish oil supplements in 302 cognitively normal older adults. The participants had to have an MMSE greater than 22, and took 1,800 mg or 400 mg EPA-DHA daily, or placebo. Treatment caused no change in a neuropsychiatric test battery of attention, sensorimotor speed, memory and executive function, in quality of life, or in mental well-being (van de Rest et al., 2008; van de Rest et al., 2008; van de Rest et al., 2009).

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 the rate of decline on either the ADAS-Cog or the CDR-SOB clinical/functional assessment. Analysis by participants' ApoE genotype indicated a slower cognitive decline in ApoE4 noncarriers, who may have been relatively less advanced in their disease (Quinn et al., 2010; Nov 2010 news). Subsequently, ApoE4 carriers were found to have smaller increases in plasma DHA and EPA, and less delivery to CSF after supplementation, than noncarriers (Tomaszewski et al., 2020; Yassine et al., 2016).

This pharmacogenetic hint of a differential effect prompted several bioavailability studies at the Université de Sherbrooke, Quebec, 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 study confirmed lower plasma levels and higher oxidation rates, contributing to a shorter half-life of DHA in ApoE4 carriers.

The largest clinical trial of DHA is MAPT, conducted in four cities in France. This three-year, secondary prevention study in 1,680 participants began in 2008 and enrolled people 70 and older who reported a subjective memory complaint and a mild functional loss, were frail and walked slowly, but did not meet an Alzheimer's diagnosis (Carrié et al., 2012). MAPT compared three interventions—800 mg DHA and 225 mg EPA daily alone, DHA/EPA plus a multidomain behavioral intervention, multidomain behavioral intervention alone—to placebo (Gillette-Guyonnet et al., 2009). Neither intervention, alone or in combination, significantly slowed cognitive decline as measured by a composite score of four tests of recall, orientation, processing and verbal fluency (Andrieu et al., 2017). An amyloid PET substudy compared the effects of the multidomain intervention and DHA/EPA according to brain amyloid status. The multidomain intervention, with or without DHA/EPA, improved composite scores after 36 months compared to placebo in the amyloid-positive, but not -negative, subset; DHA/EPA alone had no effect in either subset (Delrieu et al., 2019; Delrieu et al., 2023). In another PET analysis, cortical amyloid was lower after two years in people who got the multidomain intervention, with or without DHA/EPA, but not in those who received DPA/EPA alone (Hooper et al., 2020). DPS/EPS had no effect on brain structure by MRI, global functional connectivity, or on a composite physical and cognitive endpoint of intrinsic capacity (Sivera et al., 2020; Perus et al, 2022; Giudici et al., 2020). As in the OmegAD study, results suggested that people with low Vitamin B status may benefit less from omega-3 supplementation (Maltais et al., 2022). In this population, low DHA/EPA was potentially associated with psychiatric disorders. Participants with low RBC DHA-EPA at baseline were more likely to be using psychotropic drugs, and those who increased DHA-EPA after treatment were less likely (Gallini et al., 2019).

A subsequent analysis of MAPT data suggested higher odds of cognitive decline for people with low DHA/EPA levels (Bowman et al., 2019). Lower serum DHA was also correlated with more cerebral amyloidosis and atrophy (Yassine et al., 2016; Aug 2016 news). In response to those findings, MAPT investigators in April 2018 began LO-MAPT. This 18-month study planned to enroll 400 older adults with low DHA/EPA status and randomize them to 1.53 g/day DHA/EPA or placebo. Participants had to have subjective memory complaints or a family history of AD. The primary outcome is change in a cognitive composite of scores on the Free Cued and Selective Reminding Test, MMSE, and Category Naming Test. The trial offered an 18-month open-label extension. It was completed in 2020, after enrolling 774 participants.

From 2009 to 2011, the company NeuroBioPharm Inc. ran a six-month trial at 14 different sites in Canada to compare soft-capsule formulations of fish oil and krill oil, each containing 100 mg DHA, to placebo in 175 people with mild to moderate Alzheimer's disease. Krill oil contains DHA and EPA in a form claimed to be more bioavailable than fish oil (e.g. Schuchardt et al., 2011). This trial used the Neuropsychological Test Battery as primary outcome; data have not been published.

Between 2013-2015, a study in Taiwan tested six months of daily DHA, EPA, or the combination, against placebo in 163 people with mild cognitive impairment or AD dementia. Doses of 0.7 g/day DHA and 1.6 g/day EPA had no effect on cognitive function or depressive symptoms (Lin et al., 2022). In a placebo-controlled study of 240 Chinese people with mild cognitive impairment, supplementation with 800 mg/day DHA, folic acid, or both for six months improved cognition; the benefit disappeared after supplementation stopped (Li et al., 2021; Bai et al., 2024).

One DHA study, at Oregon Health and Science University, started in May 2014. According to published baseline data, the trial recruited 102 people age 75 and older who were cognitively impaired but did not have dementia, and suboptimal blood levels of DHA and EPA of less than 110 μg/ml. Participants were randomized to receive a three-year course of 1.65 grams/day of EPA plus DHA or soybean oil placebo (Bowman et al., 2019). Seeking to understand DHA's effect on vascular cognitive aging, this trial used white-matter hyperintensity as primary outcome; secondary and other outcome measures included other brain imaging modalities as well as blood-based indicators of endothelial health and neuropsychological tests. Top-line results were presented at the 2020 CTAD. Supplementation failed to slow accumulation of white-matter hyperintensities in the 45 placebo and 42 treated participants who had a least one follow-up MRI. At the end of the study, 24 of the treatment group had plasma DHA+EPA levels greater than 110 μg/ml. In a prespecified analysis, this group had fewer white-matter hyperintensities and maintained better white-matter integrity than the placebo group. There were no differences in total brain volume, ventricular volume, medial temporal lobe atrophy, excessive cognitive functions, or adverse events. Full results are published (Shinto et al., 2024). Numerically, white-matter lesions accumulated, and white-matter integrity was lost, more slowly in the DHA than the placebo group; however, the difference was not significant. The subset of ApoE4 carriers had significantly less annual decline in white-matter integrity after DHA supplementation.

In June 2016, a pilot study at the University of Southern California began evaluating how much of a DHA supplement enters the central nervous system, and whether CSF levels are influenced by ApoE4 status (for review, see Yassine et al., 2017). The trial enrolled 31 adults older than 55 with a family history of dementia, who took 2 g DHA per day or placebo for 26 weeks. The primary outcome was change in CSF DHA before and after supplementation. According to published results, this dose of DHA resulted in a 200 percent increase in plasma DHA compared to placebo, but only a 28 percent increase in CSF DHA (Arellanes et al., 2020). ApoE4 carriers had slightly lower CSF DHA. For EPA, CSF levels increased 43 percent, but were significantly lower in ApoE4 carriers than in noncarriers. Other endpoints including brain volume and cognitive scores did not differ between supplement and placebo groups.

In September 2018, the same group began a larger follow-up study in 368 healthy adults age 60-80, who have at least one dementia risk factor, and limited seafood intake. Half are to be ApoE4 carriers. Participants take 2g DHA or placebo daily for two years. After six months of treatment, investigators will analyze CSF fatty acids in 168 participants, to determine the effect of their ApoE genotype on supplementation. Changes in MRI measures of structural and functional connectivity and cognition will be assessed in all participants at two years. The study will run through 2025. The trial protocol and baseline data are published (Yassine et al., 2023). The study ended in May 2024, and results were presented at the October 2024 CTAD meeting. Only about sixty percent of participants finished the study, with many drop-outs due the COVID pandemic. In the 225 completers, DHA treatment increased the CSF DHA/AA ratio independent of ApoE4 genotype. The response to supplementation varied widely among participants. Hippocampal volume, and RBANS scores did not change with treatment. In E4 carriers only, an increase in CSF DHA/AA ratio during the study was associated with a modest increase in RBANS, This association held in both supplement and placebo groups. Data on structural and functional connectivity is not available yet.

For details of clinical trials of DHA in Alzheimer's, see clinicaltrials.gov.

Last Updated: 25 Nov 2024

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References

News Citations

  1. First Trial of Fish Fats Shows Promise for Early AD
  2. Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field
  3. Less Salmon, More Plaques? Link Between Omega-3s and Aβ Reinvigorates Fish Oil Debate

Paper Citations

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External Citations

  1. Li et al., 2021
  2. clinicaltrials.gov

Further Reading

Papers

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