APOE and Alzheimer disease: For example, ε3ε4 and ε4ε4 genotypes are associated with increased risks of Alzheimer disease, hypercholesterolemia, and ischemic heart disease (IHD), whereas the ε2ε3 allele has been found to be protective against hypercholesterolemia and IHD.22 A separate study found that the ε4 genotype is associated with a more pronounced cognitive decline over time in those with late-onset Alzheimer disease.24 Machine learning techniques have been used to identify further variants which modulate the APOE loci, such as the SH3BP4 gene, which may protect against the development of Alzheimer disease.19,27