Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses

Am J Clin Nutr. 2022 Dec 19;116(6):1492-1506. doi: 10.1093/ajcn/nqac236.


Background: The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established.

Objectives: The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults.

Methods: A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-β (Aβ) and tau] were considered as outcomes in regression models.

Results: Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aβ and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aβ accumulation (adjusted β = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted β = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted β = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers.

Conclusions: Longitudinally, low ω-3 index was associated with greater Aβ accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at as NCT00106899.

Keywords: Alzheimer disease; biomarkers; brain imaging; cognition; docosahexaenoic acid; eicosapentaenoic acid; mild cognitive impairment; omega-3.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease* / diagnostic imaging
  • Amyloid beta-Peptides
  • Apolipoprotein E4 / genetics
  • Biomarkers
  • Brain / diagnostic imaging
  • Cognition
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / psychology
  • Cross-Sectional Studies
  • Erythrocytes
  • Fatty Acids, Omega-3*
  • Female
  • Humans
  • Male
  • Neuroimaging / methods
  • Positron-Emission Tomography
  • Retrospective Studies


  • Apolipoprotein E4
  • Amyloid beta-Peptides
  • Biomarkers
  • Fatty Acids, Omega-3

Supplementary concepts

  • Alzheimer disease, familial, type 3

Associated data