The following is a summary of “Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease,” published in the February 2023 issue of the Neurobiology of Aging by Fan et al.

Only people of European descent carry the rare missense APOE mutation (L28P; APOE*4Pittsburgh), which has been linked to late-onset Alzheimer’s disease (LOAD). However, L28P’s independent genetic relationship is cloudy because of its linkage disequilibrium with APOE*4 (C112R). The first study linking L28P to LOAD risk involved a few participants. Although L28P has only been identified in the heterozygous condition of APOE*4 carriers and 3/4 is the most common genotype harboring the APOE*4 allele, were-evaluated this connection in a large case-control sample of 15,762 White U.S. participants and studied its independent effect in APOE 3/4 subjects. Around three times as many AD cases as cognitively normal controls were L28P heterozygotes, all carrying APOE*4. 

After considering age and gender, the pooled OR in a meta-analysis was 2.87 (95% CI, 1.34-6.13; = 0.0066). The effect was not attributable to APOE*4, as the OR in the age- and sex-adjusted meta-analysis of APOE 3/4 participants was 1.53 (95% CI: 0.70 – 3.36; P = 0.28). 4,138 patients with the 3/4 genotype (12.5% power at α = 0.05) compared to the needed sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α = 0.05 and 80% power suggests that this is the primary reason for the lack of statistical significance. 

Previous experimental results show that the L28P mutation causes significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress, supporting researchers’ data that this mutation has an independent genetic effect on AD risk. Further studies in cell-based systems and animal models will clarify its functional significance in the pathogenesis of AD.

Source: sciencedirect.com/science/article/pii/S0197458022002354