Affiliations: [a] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| [b] NHLBI’s Framingham Heart Study, Framingham, MA, USA
| [c] Department of Neurology, Boston University School of Medicine, Boston, MA, USA
| [d] Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA
Correspondence:
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Correspondence to: Dr. Gina Peloso, PhD, Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. E-mail: gpeloso@bu.edu and Sudha Seshardi, MD, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, USA. E-mail: seshadri@uthscsa.edu.
Abstract: Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer’s disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40–60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOE ɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.
Keywords: Alzheimer’s disease, association studies in genetics, cohort studies, risk factors in epidemiology
