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.

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.

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.

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.