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Background: Some observational studies indicated the associations of relative carbohydrate, sugar, fat, and protein intake and Alzheimer’s disease (AD). But it remains unclear whether the associations are causal. Objective: This study aimed to identify the effects of relative carbohydrate, sugar, fat, and protein intake in the diet on AD. Methods: A two-sample Mendelian randomization was employed. Finally, 14 independent lead SNPs remained in the Social Science Genetic Association Consortium. These SNPs of relative carbohydrate, sugar, fat, and protein intake at the level of genome-wide significance (p <  5×10–8) were used as instrumental variables. The summary data for AD were acquired from the International Genomics of Alzheimer’s Project with a total of 54,162 individuals (17,008 AD patients and 37,154 control participants). Results: This two-sample Mendelian randomization indicated that increased relative protein intake (per 1 standard deviation) causally decreased the AD risk (OR = 0.48, 95% CI: 0.24–0.95, p = 0.036), and increased relative fat intake may decrease the risk of AD (OR = 0.22, 95% CI: 0.06–0.86, p = 0.029). No statistical significance with AD risk was seen for relative carbohydrate or relative sugar intake. Conclusion: A higher relative intake of protein can causally reduce the risk of AD in the elderly. Additionally, a higher relative intake of fat may be protective against AD. No evidence showed that AD was associated with relative carbohydrate and sugar intake.

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