Re‐evaluation of the genetic role of a rare APOE variant (L28P; APOE^*4Pittsburgh) in late‐onset Alzheimer disease

Background A rare missense APOE variant (L28P; APOE * 4Pittsburgh) has been reported to be a risk factor for Alzheimer’s disease (AD). However, sinceL28P has been observed only among APOE * 4 carriers, its independent genetic association is uncertain. In this study, we re‐evaluated this association in a large case‐control sample of 15,762 U.S. Whites aged ≥60 years and investigated its independent effect. Method Samples were derived from three sources: University of Pittsburgh, Alzheimer’s Disease Sequencing Project and the Gingko Evaluation Memory Study. Due to variation in the age distribution between cases and controls in the three studies, each study sample was analyzed separately, and the results then combined by meta‐analysis. To distinguish the independent effect of L28P from APOE * 4, we restricted the analysis to subjects with the APOE 3/4 genotype, as L28P has been observed only in the heterozygous state in the APOE * 4‐background and 3/4 is the most common genotype containing the APOE * 4 allele. Result A total of 80 L28P heterozygotes were observed in the combined case‐control sample, all in those containing only the APOE * 4 allele, confirming the complete linkage disequilibrium between the two sites. The age‐ and sex‐adjusted meta‐analysis odds ratio (OR) was 2.87 (95% CI: 1.34 – 6.13; p = 0.0066). There were a total of 4,138 cases and controls with the 3/4 genotype. The age‐ and sex‐adjusted meta‐analysis OR was 1.53 (95% CI: 0.70 – 3.36; p = 0.28). The lack of significance is mainly due to the low power with the ∼4,100 sample size (12% power at α = 0.80), as compared to the required sample size of ∼151,000 to detect an OR of 1.5 at α = 0.80. Conclusion Even with non‐significant p‐value, the OR of 1.53 among 3/4 subjects suggests that the effect of L28P on AD risk is independent of APOE * 4. Our genetic finding is reinforced by an earlier experimental finding showing that this mutation leads to significant structural and conformational alterations in ApoE and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress (J Biol Chem 2014; 289:12931). Additional studies in cell‐based systems and animal models will help to delineate its functional significance in the AD etiology.