APOE. Genotyping alleles E2, E3 and E4 [1 gene]

Allele E4 of the APOE gene represents the best documented genetic risk factor in association with Alzheimer’s disease (AD), mainly in familial and late-onset cases, but with increased prevalence also in sporadic and early-onset cases. Disease inheritability in AD is estimated to be around 80%, of which APOE4 accounts for 27.3%. The risk of developing the disease in carriers compared with that of non-carriers has been estimated to be up to three times in heterozygotes (APOE3/4 genotype) and around 15 times higher in homozygotes (APOE4/4 genotype). This dose-dependent effect is also manifested in age of onset of the disease: the presence of one E4 allele in heterozygosis is associated with up to 5 years earlier onsets, while two E4 alleles in homozygosity are associated with up to 10 years earlier onsets.

A recent study on a large cohort of patients with this disease, including more than 3,000 individuals in which it was pathologically confirmed, has postulated that homozygous carriers of the E4 allele (APOE4/4) represent a singular form of Alzheimer’s disease, since, in comparison with homozygous carriers of the E3 allele, almost all of them showed pathological signs of the disease and high levels of disease-specific biomarkers from age 55 onwards. By age 65, almost all of them had abnormal amyloid levels in cerebrospinal fluid, and 75% of them were positive on amyloid examination, with a higher prevalence at advanced ages.

The APOE genotype provides a complementary value to be considered when diagnosing patients with clinical features compatible with Alzheimer’s disease. Moreover, it is worth mentioning that it can be useful for therapeutic patient management. The use of drugs such as lecanemab is generally not recommended in patients with the APOE4/4 genotype due to the risk of adverse events [https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi].

Although the E4 allele of the APOE gene constitutes the main genetic risk factor for AD, its presence is neither necessary nor sufficient for disease development. Likewise, its presence or absence does not exclude the possibility that the patient could carry any other genetic alterations that can cause dementia, nor is it useful to differentiate AD from other dementia types. Its use for the assessment of asymptomatic patients is generally not recommended.