Post by Anastasia Sares

What's the science?

Many studies have shown a relationship between lifestyle factors and cardiovascular risk factors— like high cholesterol or triglycerides— and Alzheimer’s disease. This connection may be, in part, a result of genetic predisposition. There is already one genetic variant in a gene called APOE (the strongest known risk variant for Alzheimer’s disease) which encodes a protein involved in cholesterol metabolism. This variant is known to be linked to both cardiovascular health and to Alzheimer’s disease. However, it is unclear whether there are other genetic variants like APOE that are linked to both cardiovascular risk factors and the development of Alzheimer’s disease. This week in Acta Neuropathologica, Broce and colleagues set out to identify pleiotropic genes, jointly associated with both cardiovascular health and Alzheimer’s disease risk, and specifically which cardiovascular risk factors are associated with the development of Alzheimer’s disease.

How did they do it?

The authors made use of large publicly available genome-wide association data from studies reporting both Alzheimer’s disease risk and cardiovascular outcomes. They first assessed ‘pleiotropic enrichment’ by analyzing whether Alzheimer’s disease risk increased as a function of cardiovascular risk factors. Pleiotropy is when one gene is associated with two or more distinct phenotypes. The cardiovascular risk factors included triglyceride count, coronary artery disease, body mass index, type 2 diabetes, waist hip ratio, total cholesterol and high- and low-density lipoproteins. Then, they performed a genome-wide meta-analysis using a large dataset with both genetic data and clinical information (Alzheimer’s disease and cardiovascular health) to identify significant pleiotropic genetic variants (i.e. single-nucleotide polymorphisms (SNPs)) that were significantly associated with both Alzheimer’s status and cardiovascular risk factors. They examined these SNPs across two other datasets, a replication dataset and another proxy dataset for Alzheimer’s disease (where parental status of Alzheimer’s disease was provided) to ensure that the association was consistent, both in confirmed cases of Alzheimer’s and people at risk for Alzheimer’s. Finally, they checked whether these pleiotropic SNPs actually altered gene expression in tissue samples (brain and blood), and whether the related gene was more highly expressed in brains of individuals with Alzheimer’s than in normally aging adults.

What did they find?

The authors first assessed ‘pleiotropic enrichment’ to determine whether genetic variants associated with Alzheimer’s disease risk would increase or be enriched as a function of cardiovascular risk factors. The authors found that the strongest pleiotropic enrichment for Alzheimer’s disease risk occurred as a function of triglycerides, high and low density lipoprotein as well as total cholesterol, suggesting a strong genetic overlap between plasma lipids and Alzheimer’s disease. Other cardiovascular health risks, like body mass index and type 2 diabetes, showed little to no overlap with Alzheimer’s disease risk. The authors identified 90 SNPs in the first stage of their genome-wide meta-analysis that jointly conferred risk for both cardiovascular outcomes and Alzheimer’s disease. Of these 90 SNPs, the authors were able to replicate three of the novel pleiotropic SNP associations across all datasets (these were variants within MINK1, MBLAC1, and DDB2 genes). Further, they found that these genes were differentially expressed in both Alzheimer’s disease and healthy control participants. One possible explanation for the relationship between plasma blood lipids and Alzheimer’s disease is that cholesterol is processed differently in the body and the brain. The blood-brain barrier normally keeps these processes separate, however high cholesterol may damage this barrier resulting in a predisposition to Alzheimer’s disease.