Prediction of cognitive outcome and progression to dementia using ω6‐PUFA/ω3‐PUFA ratio

INTRODUCTION The polyunsaturated fatty acids (PUFAs) omega‐6 (ω6) and omega‐3 (ω3) are linked to cognitive performance and Alzheimer's‐type dementia (DAT), but ω3‐PUFA supplementation offers limited benefits. We propose that the ω6‐PUFA/ω3‐PUFA ratio better explains cognitive decline and DAT risk. METHODS PUFA profiles were examined in the AgeCoDe cohort ( n = 3327) and MAPT trial ( n = 1679). Cox and linear mixed models evaluated associations of individual PUFAs and the ω6‐PUFA/ω3‐PUFA ratio with DAT progression and cognitive decline. Mendelian randomization (MR) assessed genetic causal effects. The effect of ω3‐PUFA on ω6‐PUFA levels was analyzed. RESULTS Higher ω6‐PUFA/ω3‐PUFA ratio increased DAT risk beyond ω3‐PUFA levels alone. A baseline high (detrimental) ratio predicted faster cognitive decline, whereas longitudinal improvements slowed decline. MR supported a genetic non‐causal link. Higher ω3‐PUFA levels correlated with lower ω6‐PUFA species. DISCUSSION The ω6‐PUFA/ω3‐PUFA ratio better predicts cognitive decline and DAT progression than individual PUFAs, suggesting that dietary adjustments may help prevent dementia.