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Cited by 764Fatty Acid Research and HealthDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: A Randomized Trial

Open access
Quinn, Joseph F., Raman, Rema, Thomas, Ronald G., Yurko-Mauro, Karin, Nelson, Edward B., Van Dyck, Christopher, Galvin, James E., Emond, Jennifer +4 more·2010·JAMA
DOI 10.1001/jama.2010.1510PMC PMC3259852
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Abstract

CONTEXT: Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. OBJECTIVE: To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer's Disease Cooperative Study. INTERVENTION: Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. MAIN OUTCOME MEASURES: Change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). RESULTS: A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). CONCLUSION: Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00440050.

AI snapshot

Written from the paper’s full text.

TL;DR

In adults with mild to moderate Alzheimer disease, 18 months of algal DHA supplementation at 2 g/d did not slow cognitive or functional decline compared with placebo. Plasma and CSF DHA increased substantially, but primary clinical and MRI outcomes showed no treatment benefit.

Key findings

  • DHA did not affect the co-primary outcomes: ADAS-cog increased by 7.98 points (95% CI, 6.51–9.45) with DHA vs 8.27 points (95% CI, 6.72–9.82) with placebo (P = .41); CDR sum of boxes increased by 2.87 points (95% CI, 2.44–3.30) vs 2.93 points (95% CI, 2.44–3.42) (P = .68).
  • In the MRI substudy (DHA: 53; placebo: 49), total brain volume declined by 24.7 cm³ (95% CI, 21.4–28.0) with DHA vs 24.0 cm³ (95% CI, 20–28) with placebo (P = .79); annual decline was 1.32% vs 1.29%.
  • Plasma phospholipid DHA rose from 3.18 to 9.82 weight percentage at 18 months in the DHA group (207% increase, P < .001), and CSF DHA rose 38% (2.53 to 3.46 weight percentage; P < .001).
  • In an exploratory APOE ε4–negative subgroup, DHA was associated with less ADAS-cog decline (6.23 vs 10.11 points; P = .03) and less MMSE decline (P = .03), but not with CDR sum of boxes, ADCS-ADL, NPI, or brain atrophy.

Methods

  • Randomized, double-blind, placebo-controlled trial conducted by the Alzheimer’s Disease Cooperative Study at 51 US sites between November 2007 and May 2009; participants had probable Alzheimer disease, MMSE 14–26, low baseline DHA intake (≤200 mg/d), and no DHA/omega-3 supplement use.
  • Participants were randomized 60% to algal DHA 2 g/d or 40% to identical placebo for 18 months; 402 were randomized (238 DHA, 164 placebo), and 295 completed while taking study medication (DHA: 171; placebo: 124).
  • Co-primary outcomes were change in ADAS-cog and CDR sum of boxes, analyzed primarily with linear mixed-effects models in an intent-to-treat population; MRI substudy and CSF fatty acid substudy were also performed.

Limitations

  • Stated: attrition was 28% in the DHA group and 24% in the placebo group, hypothesized to be driven by perceived lack of efficacy; the MRI substudy was a convenience sample rather than a statistical sample of the overall population.
  • Stated: the APOE ε4–negative subgroup finding was exploratory, not adjusted for multiple comparisons, and not seen across all outcomes; the trial cannot rule out benefit if DHA were started earlier, before overt dementia or in mild cognitive impairment.
  • Evident from the text: site physicians were more likely to guess that participants were receiving DHA (21.9% vs 11.3% for placebo; P = .02), suggesting possible partial unblinding, and the high dropout rate may limit generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jama.2010.1510

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    DHA supplementation compared with placebo did not affect the rate of brain atrophy (total brain volume decline) in the MRI subsample.

    “In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA.”
    Quote in the paperSubstantial claim
  • Findingown data

    DHA supplementation compared with placebo did not slow the rate of functional/global decline, as measured by CDR sum of boxes, in individuals with mild to moderate Alzheimer disease.

    “The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44–3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44–3.42 points) for the placebo group (linear mixed-effects model: P = .68).”
    • Also stated in: § Co-primary Outcome Measures · plain
      “The rate of points change on CDR sum of boxes over 18 months was 2.93 (95% CI, 2.44–3.42) for the placebo group compared with 2.87 (95% CI, 2.44–3.30) for the DHA group (linear mixed-effects model: P = .68; Figure 2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    DHA supplementation had no effect on total ventricular volume change in the MRI substudy.

    “total ventricular volume (9.1 cm3 [95% CI, 7.7–10.4 cm3] in the DHA group vs 8.1 cm3 [95% CI, 6.4–9.8 cm3] in the placebo group; P = .55).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Confirmatory generalized estimating equations and ANCOVA analyses did not show a benefit of DHA treatment.

    “Confirmatory generalized estimating equations and ANCOVA analyses did not show a benefit of treatment with DHA.”
    Quote in the paperSubstantial claim
  • Findingown data

    There is no evidence that DHA treatment had an adverse effect in this trial.

    “there is no evidence that DHA treatment had an adverse effect in this trial.”
    Quote in the paperNot a substantial claim
  • The quote only partly states this claim. 1
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 22

  • The quote only partly states this claim.

    Findingown data

    DHA supplementation had no effect on NPI change over 18 months.

    “The NPI changed by 2.93 points (95% CI, 0.92 to 4.94 points) over 18 months for the DHA group compared with 5.09 points (95% CI, 2.49 to 7.69 points) for the placebo group (linear mixed-effects model: P = .11; Figure 2D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The apparent treatment effect in APOE ε4-negative participants was not seen on CDR sum of boxes, ADCS-ADL, NPI, or brain atrophy.

    “but was not present on the CDR sum of boxes, the ADCS-ADL, or the NPI (eTable 2).”
    • Also stated in: § COMMENT · plain
      “Furthermore, the apparent treatment effect in APOE ε4–negative participants was not seen on the CDR sum of boxes, ADCS-ADL, NPI, or brain atrophy, weakening the interpretation that this effect is clinically meaningful.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cerebrospinal fluid DHA increased by 38% in the DHA group from 2.53 to 3.46 weight percentage at 18 months (P < .001), but not in the placebo group.

    “a significant 38% increase in cerebrospinal fluid DHA was observed in the DHA group (2.53 weight percentage at baseline and 3.46 weight percentage at 18 months; P < .001) but not in the placebo group (2.50 weight percentage at baseline and 2.17 weight percentage at 18 months; P = .79).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proportion of individuals with at least 1 adverse event, serious adverse event, hospitalization, and death were similar in the active and placebo groups.

    “The proportion of individuals with at least 1 adverse event, serious adverse event, hospitalization, and death were similar in the active and placebo groups (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ad hoc linear mixed-effects analyses including both sex and baseline MMSE score as covariates did not show a benefit of DHA on ADAS-cog (P = .61), CDR sum of boxes (P = .69), or ADCS-ADL (P = .38).

    “The ad hoc linear mixed-effects analyses including both sex and baseline MMSE score as covariates also did not show a benefit of treatment with DHA on the ADAS-cog (P = .61), CDR sum of boxes (P = .69), or ADCS-ADL (P = .38).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plasma phospholipid DHA increased in the DHA treatment group from 3.18 weight percentage at baseline to 9.80 at 6 months, 10.20 at 12 months, and 9.82 at 18 months (207% increase, P < .001), with no significant change in the placebo group.

    “As expected, plasma phospholipid DHA increased in the DHA treatment group from 3.18 weight percentage at baseline to 9.80 weight percentage at 6 months, 10.20 weight percentage at 12 months, and 9.82 weight percentage at 18 months (207% increase, P < .001) with no significant change in plasma phospholipid DHA in the placebo group (3.13 weight percentage at baseline and 3.12 weight percentage at 18”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There was a single adverse event of increased INR in the placebo group.

    “There was also a single adverse event of increased INR in the placebo group.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    No further cases of study drug-associated INR instability were noted.

    “No further cases of study drug–associated INR instability were noted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    During the blinded phase, thrombotic events were occurring at a rate higher than expected overall.

    “The data and safety monitoring board also noted during the blinded phase of the trial that thrombotic events were occurring at a rate higher than expected overall, and such events were monitored closely during the trial.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    During the blinded phase, the data and safety monitoring board noted that 3 individuals taking warfarin (of 32 taking warfarin at randomization) reported subtherapeutic INR after initiating study drug, and the protocol was revised to require monthly INR testing.

    “During the blinded phase of the trial, the data and safety monitoring board noted that 3 individuals taking warfarin (of a total of 32 participants taking warfarin at the time of randomization) reported subtherapeutic international normalized ratio (INR) after initiating study drug, and the protocol was revised to require monthly INR testing, which was reported to the medical monitor for all”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Baseline MMSE score was unbalanced between DHA and placebo groups and associated with rates of change on ADAS-cog and CDR sum of boxes, and was included as a covariate in primary analyses.

    “For the primary analysis, baseline MMSE score was found to be unbalanced between groups and associated with the rates of change in scores on the ADAS-cog and CDR sum of boxes, and was therefore included in the model as a covariate in the analysis of these co-primary outcome measures.”
    • Also stated in: § Co-primary Outcome Measures · plain
      “For the primary linear mixed-effects analysis of the rate of change of ADAS-cog and CDR sum of boxes, baseline MMSE score was the only covariate qualifying for inclusion in the model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The MRI substudy population is a convenience sample, not a statistical sample of the overall study population.

    “This subpopulation represents a convenience sample, relying on participant volunteerism and site expertise rather than random selection to guide enrollment.”
    • Also stated in: § COMMENT · plain
      “it is still important to note that the MRI study population is not a statistical sample of the overall study population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Sex was also unbalanced between groups and associated with rate of change on primary outcome measures, prompting an ad hoc analysis including both sex and MMSE score as covariates.

    “Although it was not prespecified as a candidate covariate, sex was also found to be both unbalanced between groups and associated with rate of change on the primary outcome measures, prompting an ad hoc analysis including both sex and MMSE score as covariates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    In the blinding analysis, the majority of study partners (48.5%), study coordinators (50%), and site physicians (59.2%) responded "do not know"; site physicians were more likely to guess that participants in the DHA group were receiving treatment (21.9% vs 11.3%, P = .02).

    “When asked to guess treatment assignment for each participant at the final study visit, the majority of study partners (48.5%), study coordinators (50%), and site physicians (59.2%) responded “do not know.””
    • Also stated in: § Blinding Analysis · plain
      “but site physicians were more likely to guess that participants in the DHA group were receiving treatment (21.9% for DHA and 11.3% for placebo; P = .02).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The trial was randomized, double-blind, placebo-controlled.

    “A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14–26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study.”
    • Also stated in: § METHODS · plain
      “This randomized, double-blind, placebo-controlled trial was conducted by the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of academic medical centers and private Alzheimer disease clinics funded by the National Institute on Aging to conduct clinical trials on Alzheimer disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Randomization was achieved with a centralized interactive voice response system using a block design with block size of 5 (3 DHA, 2 placebo).

    “Randomization was achieved with a centralized interactive voice response system, using a block design with a block size of 5 (3 in the DHA group and 2 in the placebo group).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The primary analysis was an intent-to-treat analysis including all randomized participants, analyzed as randomized regardless of medication adherence.

    “The primary analysis was an intent-to-treat analysis including all randomized participants. That is, participants were analyzed in the group to which they were randomized, regardless of medication adherence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The adequacy of blinding was assessed by questionnaires completed by caregivers, study coordinators, and site physicians.

    “The adequacy of blinding was assessed by questionnaires completed by caregivers, study coordinators, and site physicians.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Eicosapentaenoic acid is virtually absent from the brain.

    “The other major omega-3 fatty acid found in fish, eicosapentaenoic acid, is virtually absent from the brain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    DHA modifies the expression of Alzheimer-like brain pathology in mouse models.

    “DHA modifies the expression of Alzheimer-like brain pathology in mouse models.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    An APOE genotype-specific effect of DHA is plausible.

    “so an APOE genotype–specific effect is plausible.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The MRI sequence and methods for across-site standardization and quality control were those used in the ADNI study.

    “The MRI sequence, as well as methods for across-site standardization and quality control, were those used in the ADNI study.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Jack CR Jr Bernstein MA Fox NC The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods J Magn Reson Imaging 2008 27 4 685 691 18302232 PMC2544629

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mutant amyloid precursor protein (APP) Tg2576 mice, DHA supplementation reduced amyloid β pathology and the neuritic damage associated with amyloid β plaques.

    “In mutant amyloid precursor protein (APP) Tg2576 mice, DHA supplementation reduced amyloid β pathology11 as well as the neuritic damage associated with amyloid β plaques.12”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Lim GP Calon F Morihara T A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model J Neurosci 2005 25 12 3032 3040 15788759 PMC6725084

      Not checked in the free run.

    • cites [12] Calon F Lim GP Yang F Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model Neuron 2004 43 5 633 645 15339646 PMC2442162

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The planned subgroup analyses were intent-to-treat analyses.

    “The planned subgroup analyses were intent-to-treat analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because healthy elderly individuals do not experience significant cognitive decline in this time frame, the absence of a cognitive effect does not exclude the possibility of a neuroprotective effect of DHA in individuals at risk of decline.

    “Because these healthy elderly individuals do not experience significant cognitive decline in this time frame, however, the absence of a cognitive effect does not exclude the possibility of a neuroprotective effect of DHA in individuals at risk of decline.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some have suggested that increased oxidative burden is a risk in DHA supplementation studies.

    “Some have suggested that increased oxidative burden is a risk in DHA supplementation studies34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Song JH Miyazawa T Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid oil Atherosclerosis 2001 155 1 9 18 11223421

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Of 555 individuals screened, 402 met the study criteria and were randomized, 238 to DHA and 164 to placebo.

    “Of 555 individuals screened, 402 met the study criteria and were randomized, 238 to DHA and 164 to placebo.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The primary hypothesis analysis was duplicated using SAS version 9 for verification purposes.

    “For the primary hypothesis, the analysis was duplicated by using SAS version 9 (SAS Institute Inc, Cary, North Carolina) for verification purposes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Over 18 months, 67 participants in the DHA group (28%) and 40 participants in the placebo group (24%) discontinued taking the study drug, with the minority discontinuing due to adverse events.

    “Over the course of 18 months, 67 participants in the DHA group (28%) and 40 participants in the placebo group (24%) discontinued taking the study drug, with the minority discontinuing due to adverse events (Figure 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The attrition rate is within the spectrum seen in recent 18-month trials for Alzheimer disease, higher than seen in a study of homocysteine-lowering B vitamins, but lower than reported with tarenflurbil.

    “This attrition rate is within the spectrum seen in recent 18-month trials for Alzheimer disease, higher than seen in a study of homocysteine-lowering B vitamins,28 but lower than reported with tarenflurbil.29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Aisen PS Egelko S Andrews H A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease Am J Geriatr Psychiatry 2003 11 2 246 249 12611755

      Not checked in the free run.

    • cites [29] Green RC Schneider LS Amato DA Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial JAMA 2009 302 23 2557 2564 20009055 PMC2902875

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Among the MRI substudy, 170 had an MRI at baseline and 102 had MRIs at baseline and 18 months (DHA: 53; placebo: 49).

    “Among the individuals participating in the MRI substudy (170 had an MRI at baseline and 102 had MRIs at baseline and 18 months [DHA group: 53; placebo group: 49])”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In mice carrying 3 mutant transgenes (App, Ps1, Tau) associated with Alzheimer disease pathology, DHA supplementation reduced both amyloid β and tau pathology.

    “In mice carrying 3 mutant transgenes (App, Ps1, Tau) associated with Alzheimer disease pathology, DHA supplementation reduced both amyloid β and tau pathology.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Green KN Martinez-Coria H Khashwji H Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels J Neurosci 2007 27 16 4385 4395 17442823 PMC6672302

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHA is enriched in synaptic fractions and is reduced in the brains of patients with Alzheimer disease.

    “DHA is enriched in synaptic fractions and is reduced in the brains of patients with Alzheimer disease.9,10”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Prasad MR Lovell MA Yatin M Dhillon H Markesbery WR Regional membrane phospholipid alterations in Alzheimer’s disease Neurochem Res 1998 23 1 81 88 9482271

      Not checked in the free run.

    • cites [10] Söderberg M Edlund C Kristensson K Dallner G Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease Lipids 1991 26 6 421 425 1881238

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Placebo capsules were identical in appearance to DHA capsules.

    “Placebo capsules (made up of corn or soy oil) were identical in appearance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several epidemiological studies indicate that a protective effect of omega-3 fatty acids with respect to dementia may be confined to APOE ε4-negative individuals.

    “several epidemiological studies indicate that a protective effect of omega-3 fatty acids with respect to dementia may be confined to APOE ε4–negative individuals,38–40”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] Huang TL Zandi PP Tucker KL Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4 Neurology 2005 65 9 1409 1414 16275829

      Not checked in the free run.

    • cites [39] Barberger-Gateau P Raffaitin C Letenneur L Dietary patterns and risk of dementia: the Three-City Cohort Study Neurology 2007 69 20 1921 1930 17998483

      Not checked in the free run.

    • cites [40] Whalley LJ Deary IJ Starr JM n-3 Fatty acid erythrocyte membrane content, APOE epsilon4, and cognitive variation: an observational follow-up study in late adulthood Am J Clin Nutr 2008 87 2 449 454 18258638

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    A total of 402 individuals were randomized and 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124).

    “A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124).”
    Quote in the paperNot a substantial claim
36 of 36

  • The paper relies on this without support.

    The trial participants are representative of the broader population of individuals with mild to moderate Alzheimer disease.

    “Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.”
    “In summary, these results indicate that DHA supplementation is not useful for the population of individuals with mild to moderate Alzheimer disease.”

  • The paper relies on this without support.

    Increased plasma and cerebrospinal fluid DHA in the DHA group reflects increased brain DHA availability sufficient to affect Alzheimer disease pathology.

    “Despite enrollment of the target population of individuals with low baseline DHA, increase of plasma phospholipid and cerebrospinal fluid DHA in the group treated with DHA, and ample progression of randomized participants on the primary outcome measures, there was no evidence of benefit of DHA supplementation in this population.”
    “a significant 38% increase in cerebrospinal fluid DHA was observed in the DHA group (2.53 weight percentage at baseline and 3.46 weight percentage at 18 months; P < .001) but not in the placebo group (2.50 weight percentage at baseline and 2.17 weight percentage at 18 months; P = .79).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Trial dates conflict with recruitment dates

    Minor

    The abstract says the trial was conducted beginning in November 2007, but the results say recruitment began in February 2007.

  • MMSE estimate falls outside its stated confidence interval

    Minor

    The APOE ε4-negative DHA-group MMSE change is −3.36, but its stated 95% confidence interval is entirely positive. The placebo-group estimate and interval have the same sign conflict.

2 of 2

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References 44 · Cited by 764

Authors
Quinn, J. F., Raman, R., Thomas, R. G., Yurko-Mauro, K., Nelson, E. B., Van Dyck, C., Galvin, J. E., Emond, J., Jack, C. R., Weiner, M., Shinto, L., & Aisen, P. S.
Affiliations
  • Oregon Health & Science University (US)
  • Mayo Clinic (US)
Corresponding author
Quinn, Joseph F.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2010-11-03
Volume
304
Issue
17
Pages
1903
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2010.1510
PMC
PMC3259852
OpenAlex
W2079183773
Semantic Scholar
e50de26c57a87637af4b7930f7de111930306c73
Cited by
764
References
44
Citations by year
2026: 30 · 2025: 34 · 2024: 31 · 2023: 36 · 2022: 39 · 2021: 44 · 2020: 55 · 2019: 40 · 2018: 51 · 2017: 55 · 2016: 59 · 2015: 56 · 2014: 61 · 2013: 63 · 2012: 59
FWCI
52.50
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (U01‐AG10483, U01AG010483, P30AG008051, U19AG010483)
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
docosahexaenoic acid, omega-3 fatty acids, Alzheimer's disease, cognitive decline, functional decline, algal oil, dietary supplementation, brain atrophy, long-chain polyunsaturated fatty acids, ADAS-Cog, Clinical Dementia Rating, Alzheimer's disease prevention, Alzheimer's disease treatment, Alzheimer's disease risk factors, Alzheimer's disease biomarkers
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cognition Disorders, Docosahexaenoic Acids, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Treatment Outcome, Disease Progression, Dietary Supplements, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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