Polyunsaturated fatty acids, APOE genotypes, and dementia incidence and mortality among hypertensive adults - 12/07/25

Doi : 10.1016/j.tjpad.2025.100297

Yubo Zhang ^1,^{^{#
These authors contributed equally to this work.}}, Jindi Li ^2,^{^{#
These authors contributed equally to this work.}}, Shaohui Liu ¹, Quanhong Chen ², Xuexiu Wang ¹, Sisi He ¹, Yadong Wei ¹, Yunfeng Zou ^2,^3,⁴, Yunan Xu ^5,^{^{c
Tel: +86 771 5356557},}^⁎ , Lijun Wang ^3,^4,^6,^{^{b
Tel: +86 771 5358955},}^⁎ , Hao Chen ^1,^3,^4,^{^{a
Tel: +86 771 5358955},}^⁎
¹ Department of Occupational and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, China
² Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China
³ Department of Medical Research. The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China
⁵ Guangxi Key Laboratory of Environment and Health Research, Guangxi Medical University, Nanning, Guangxi 530021, China
⁶ Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China

^⁎Corresponding authors.

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Abstract

Background

Individuals with hypertension have an elevated risk of dementia. The potential protective effects of dietary polyunsaturated fatty acids (PUFAs) against dementia remain unclear. In this study, we investigate associations between blood PUFA levels and dementia outcomes, while considering the genetic predisposition among hypertensive adults.

Methods

We employed data from UK Biobank and a prospective cohort of 123,235 hypertensive participants aged 40–69 years were included for the analysis (2006–2022). Cox proportional hazards models adjusting for covariates were applied to assess the associations of blood levels of docosahexaenoic acid (DHA), N3FA, N6FA, linoleic acid (LA), total PUFA, and the N6FA/N3FA ratio with incident dementia, dementia mortality, and all-cause mortality. The analyses were also stratified by polygenic risk scores (PRS) or APOE genotype.

Results

Higher levels of DHA (HR 0.41, 95% CI 0.27–0.62), N3FA, LA, N6FA, and total PUFA were associated with significantly reduced dementia incidence (P < .001). In contrast, a higher N6FA/N3FA ratio was linked to increased dementia risk. Similar trends were observed for mortality. APOE genotype, rather than PRS, modified PUFA–dementia associations: individuals with low-to-moderate APOE risk showed greater protective effects of high PUFA levels compared to those with high-risk genotypes.

Conclusions

Among hypertensive adults, higher PUFA levels are associated with reduced risks of dementia and mortality. An imbalanced N6FA/N3FA ratio increases risk, while APOE genotype significantly modifies PUFA-related dementia outcomes.

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Keywords : UK Biobank, hypertension, polyunsaturated fatty acids, dementia, polygenic risk scores, APOE genotypes