Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their ...age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-epsilon4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-epsilon4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives greater than or equal to 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-epsilon4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval 99-100%) by age 70 among APOE-epsilon4epsilon4 carriers only, compared with 56% 40-72% and 37% 26-51% in epsilon4 heterozygous carriers and epsilon4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications. Keywords: Alzheimer, SORL1, APOE, Penetrance, Lifetime risk, Expectation-maximization algorithm, Pedigree, Missing genotypes
