Rationale for Correct Answer

The correct answer is: Carrying 2 ApoE4 alleles increases LOAD risk by 8- to 12-fold, compared with carrying 2 ApoE3 alleles

ApoE3E3 and ApoE3E4 are the most common genotypes in cognitively healthy individuals and people with AD. ApoE3E4 is the most common genotype in people with LOAD, and ApoE3E3 is the most common genotype in cognitively healthy individuals.1 ApoE2 alleles are protective and found as ApoE2E2 in 0.3% of patients with LOAD and as ApoE2E3 in 4.6%.1 However, it is important to note that carrying the ApoE4 allele does not necessarily mean a person will develop LOAD, as other genetic and environmental factors also influence disease risk. Similarly, the absence of the allele does not rule out AD, as approximately 42% of people diagnosed with AD do not carry the ApoE4 allele.2 Compared with the ApoE3 variant, the ApoE4 allele is associated with increased severity and earlier onset of AD and with faster cognitive decline and decreased survival time.3,4,5 The ApoE4 allele has a dose-dependent relationship with LOAD susceptibility.3 One ApoE4 allele confers a 2- to 3-fold increased odds of AD, whereas 2 copies (ApoE4E4) confer 8- to 12-fold increased odds of AD, compared with non-carriers.6

1. Yamazaki Y et al. Nat Rev Neurol. 2019;15:501-518.
2. Bird TD. Alzheimer disease overview. 1998 Oct 23 [Updated 2018 Dec 20]. In: Adam MP, Mirzaa GM, Pagon RA, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https//www.ncbi.nlm.nih.gov/books/NBK1161/
3. Corder EH et al. Science. 1993;261:921-923.
4. Martins CA et al. Neurology. 2005;65:1888-1893.
5. Dal Forno G et al. Neurology. 2002;58:1045-1050.
6. Myers RH et al. Neurology. 1996;46:673-677.