B-325 APOE Genetic Testing and E4 Allele Frequency in a Clinical Population: Implications for Alzheimer’s Disease Risk Stratification

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide and represents a major public health challenge driven by population aging. It is estimated that more than 50 million people currently live with dementia, with AD accounting for 60–70% of cases, and projections exceeding 150 million cases by 2050. Among the main genetic factors associated with AD, apolipoprotein E (ApoE), encoded by the APOE gene, plays a central role in lipid metabolism and in maintaining the integrity of the central nervous system. Among the APOE alleles (E2, E3, and E4), the E4 allele is the primary genetic risk factor, being associated with increased beta-amyloid deposition and greater disease severity, whereas the E2 allele exhibits a neuroprotective effect. Given the relevance of ApoE in modulating disease risk and progression, APOE genotyping has emerged as a promising tool for risk stratification and prevention. The aim of this study was to analyze the age and genotypic distribution of ApoE in a clinical population and to evaluate its potential for Alzheimer’s disease risk stratification. This observational, retrospective, and descriptive study analyzed 793 samples from a large diagnostic laboratory in São Paulo, Brazil. ApoE genotyping was performed using an in-house real-time PCR method with a qualitative allelic discrimination assay for the identification of the E2, and E4 alleles. The risk categories considered were low risk (E2E2 and E2E3), normal risk (E3E3), increased risk (E2E4 and E3E4), and high risk (E4E4). Among the 793 individuals tested, the highest proportion was observed in the =70-year age group (36.6%), followed by the 50–59 years (16.0%), 60–69 years (15.8%), 40–49 years (15.5%), 30–39 years (11.1%), and <30 years (5%) age groups. Overall, 62.7% of the individuals were female. The distribution of ApoE genotypes showed a predominance of the E3E3 genotype (440/793), regardless of sex or age group. Considering both genders, genotypes associated with the E4 allele were more frequent in older individuals. Among the 278 E4 carriers, the largest proportion was observed in individuals aged =70 years (44.6%), followed by 50–59 years (16.2%), 60–69 years (14.7%), 40–49 years (12.9%), 30–39 years (6.5%), and <30 years (5%). Among females, 154 individuals were classified in the increased-risk category (E2E4 and E3E4), with 45.4% (70/154) aged =70 years. Among males, the =70-year age group included 40 individuals with increased risk and 5 with high risk, whereas in younger age groups the high-risk category was rare or absent. These findings demonstrate that ApoE genetic testing in a clinical population is predominantly performed at older ages, where the frequency of E4 allele carriers is higher. This pattern suggests that testing is mainly used in late clinical contexts, possibly after symptom onset. Considering that the E4 allele precedes the clinical manifestations of Alzheimer’s disease by decades, expanding testing to younger age groups may enable earlier risk stratification, longitudinal monitoring, and the implementation of preventive strategies, thereby enhancing the impact of precision medicine in Alzheimer’s disease prevention.