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Background:  Previous observational studies provided conflicting results on the association between low-density lipoprotein cholesterol (LDL-C) level and the risk of Alzheimer's disease (AD).   Objective:  We used two-sample Mendelian randomization (MR) study to explore the causal associations between LDL-C level and the risks of individual, paternal, maternal, and family history of AD.   Methods:  Summary-level genetic data for LDL-C were acquired from results of the UK Biobank GWAS. Corresponding data for paternal, maternal, and family history of AD were obtained from the NHGRI-EBI Catalog of human genome-wide association studies. Data for individual AD were obtained from the MR-Base platform. A two-sample MR study was performed to explore the causal association between LDL-C level and the risks of individual, paternal, maternal, and family history of AD.   Results:  Genetically predicted LDL-C was positively associated with individual [Odds ratio (OR) = 1.509, 95% confidence interval (CI) = 1.140–1.999;  P  = 4.0 × 10 −3 ], paternal [OR = 1.109, 95% CI = 1.053–1.168;  P  = 9.5 × 10 −5 ], maternal [OR = 1.132, 95% CI = 1.070–1.199;  P  = 2.0 × 10 −5 ], and family history of AD [OR = 1.124, 95% CI = 1.070–1.181;  P  = 3.7 × 10 −6 ] in inverse variance weighted analysis. After performing weighted median and MR-Egger analysis, consistent results were observed. There was no horizontal pleiotropy in the two-sample MR analysis.   Conclusions:  High level of LDL-C may increase the risks of both individual and familial AD. Decreasing the LDL-C to a reasonable level may help to reduce the related risk.

Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease