Sustained fish intake and 21-year Alzheimer's disease risk: a target trial emulation.

Increasing oily fish intake has been proposed as a strategy for Alzheimer's disease (AD) prevention, but evidence for long-term benefit remains limited. Using observational data from 2012 cognitively healthy adults in the Framingham Heart Study Offspring cohort, we emulated a target trial of seven isocaloric fish intake strategies to estimate 21-year AD risk. We modeled repeated measures of diet and adjusted for pre-baseline diet, baseline covariates, and time-varying confounding using the parametric g-formula. The estimated 21-year AD risk ranged from 10.33% (95% confidence interval [CI]: 8.41%, 12.92%) under no fish intake to 9.98% (95% CI, 6.64%, 13.31%) under ≥ 3 servings/week. Risk ratios relative to no intervention were close to one and risk differences were close to zero across all strategies. Substituting fish for meat yielded similar results. We observed no clear long-term protective effect of sustained fish intake on AD risk, though exploratory analyses suggested a possible protective effect among older participants during earlier follow-up, warranting further investigation. This study illustrates the use of target trial emulation to estimate long-term dietary effects while accounting for time-varying confounding and competing risks in nutritional epidemiology.