Estimating the Impact of Long-Term Fish Consumption and Alzheimer’s Disease Risk: Insights From a Target Trial Emulation

Objectives: Despite mixed evidence regarding the role of fish consumption in preventing Alzheimer's disease (AD), this study seeks to clarify the long-term impact. We aim to estimate the effect of sustained fish intake on the 23-year risk of AD in cognitively healthy adults by emulating a hypothetical randomized controlled trial (RCT) using existing observational data. Methods: We outlined a protocol for a hypothetical RCT to address the causal relationship in question. Utilizing data from the Framingham Heart Study Offspring cohort (Exams 6 to 9), we adapted critical RCT design elements within an observational study context. We employed the parametric g-formula to estimate the 23-year AD risk under ten fish intake scenarios, adjusting for both baseline and time-varying confounders. These scenarios ranged from no dietary change to varying levels of fish consumption, including scenarios where red meat was replaced with fish. We explicitly listed the assumptions underlying the emulation to ensure transparency and performed sensitivity analyses to assess the robustness of our findings. Results: Among the 1966 eligible participants (mean age: 61.3 years, standard deviation (SD): 7.55 years), who averaged 1.85 servings (SD: 1.57 servings) of fish intake weekly, 89 developed AD over 23 years. The AD risk ratios, compared to no intervention, were as follows: no fish, 1.11 (95% confidence interval (CI): 1.03-1.48); ≥1 serving per week, 1.00 (95% CI: 0.95-1.00); up to ≥4 servings per week, 0.92 (95% CI: 0.63-1.12). Substituting fish for red meat resulted in risk ratios ranging from 1.02 (95% CI: 0.97-1.06) to 1.17 (95% CI: 0.74-1.75) for ≥ 1 to ≥ 4 servings per week, respectively. Conclusions: Increased fish consumption was associated with a trend toward reduced AD risk over 23 years among cognitively healthy older adults, with up to ≥ 4 servings per week. However, there was no clear risk reduction when fish replaced red meat in the diet. These findings should be interpreted with caution due to potential cohort-specific factors and high variability due to a limited number of AD diagnoses. Funding Sources: The study was supported by the United States Department of Agriculture (USDA), Agriculture Research Service (ARS) and by NIH grant.