| Title: | Higher plasma omega-6 fatty acids are associated with lower dementia risk: evidence from NMR metabolomics and Alzheimer's disease polygenic risk in the UK Biobank |
| Journal: | Frontiers in Public Health |
| Published: | 14 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42221673/ |
| DOI: | https://doi.org/10.3389/fpubh.2026.1816467 |
| URL: | https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2026.1816467/pdf |
Publication 20038
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Abstract
Background: Circulating polyunsaturated fatty acids (PUFAs) have been implicated in neurodegenerative processes, yet epidemiological evidence remains inconsistent. Genetic susceptibility to Alzheimer's disease (AD), commonly indexed by a polygenic risk score (PRS), is a major determinant of dementia risk. However, few large-scale prospective studies have jointly examined plasma fatty acid profiles and genetic liability to AD in relation to incident dementia.</p>
Objectives: To investigate the independent and combined associations of plasma omega-3 PUFAs, omega-6 PUFAs, and the omega-6/omega-3 ratio with incident dementia, and to determine whether these associations vary according to AD-PRS.</p>
Methods: We analyzed data from 81,827 UK Biobank participants with baseline nuclear magnetic resonance (NMR) metabolomics and genetic information. Plasma fatty acids were quantified using standardized NMR spectroscopy, and genetic risk for AD was assessed using the Enhanced AD-PRS. Incident dementia was identified through linked hospital admission and death registry records. Multivariable-adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models. Dose-response relationships and both additive and multiplicative interactions with AD-PRS were evaluated, alongside subgroup and sensitivity analyses.</p>
Results: Over a median follow-up of 12.1 years, 1,335 participants developed dementia. Higher plasma omega-6 concentrations were consistently associated with a lower risk of dementia, corresponding to an approximately 15% risk reduction per 1 mmol/L increase (HR 0.85, 95% CI 0.79-0.93, P < 0.001). In contrast, plasma omega-3 levels (HR 0.97, 95% CI 0.77-1.23, P = 0.81) and the omega-6/omega-3 ratio (HR 0.96, 95% CI 0.85-1.09, P = 0.55) were not significantly associated with dementia risk. AD-PRS was a strong predictor of incident dementia; however, no statistically significant interactions were observed between AD-PRS and any fatty acid biomarker. Joint analyses suggested only modest attenuation of absolute genetic risk at higher omega-6 concentrations. Findings were robust across multiple sensitivity analyses.</p>
Conclusions: Higher plasma omega-6 PUFA levels were independently associated with a clinically meaningful reduction in dementia risk, whereas omega-3 PUFAs and the omega-6/omega-3 ratio were not. Although elevated omega-6 modestly reduced absolute risk among individuals with high genetic susceptibility to AD, no meaningful gene-nutrient interaction was detected. Further mechanistic and interventional studies are warranted to elucidate underlying pathways.</p>
17 Keywords
- Aged
- Alzheimer Disease
- Dementia
- Fatty Acids, Omega-3
- Fatty Acids, Omega-6
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Humans
- Magnetic Resonance Spectroscopy
- Male
- Metabolomics
- Middle Aged
- Prospective Studies
- Risk Factors
- UK Biobank
- United Kingdom
4 Authors
- Li Luo
- Siyin Gong
- Dan Liu
- Kunyan Zhou
1 Application
| Application ID | Title |
|---|---|
| 506790 | Integrating genetics, omics data, and epidemiological data to enhance comprehensively the etiology of female reproductive disease and postmenopausal women's noncommunicable diseases(NCDs) |
Enabling scientific discoveries that improve human health