Jiyeon Song, Serina Yan, Sophia Liu, Adhvaith Sridhar, Kijung Sung, Joshua Pillai, Chengbiao Wu
We found that VEPs were consistently correlated with age at onset (AAO) among EOAD patients and the amyloid-β (Aβ) 42/Aβ40 ratio biomarker. Regarding the ratio, we observed discrepancies in the predictor variables influencing the Aβ42/Aβ40 ratio, with conflicting evidence as to whether the elevated ratio stems from diminished Aβ40 levels or augmented Aβ42 production. We also identified that with increased predicted pathogenicity, there were decreased Aβ38 levels. Conversely, this study found no direct correlations with Aβ37 and Aβ43. Lastly, structural studies show characteristics of both DN and LoF mechanisms, as there are variants positioned in buried hydrophobic domains and charged surfaces.
INTRODUCTION: Early-onset Alzheimer's disease (EOAD) is mostly caused by mutations in presenilin-1/2 (PSEN1, PSEN2) and amyloid precursor protein (APP) genes. Both genetic and experimental evidence have supported the PSEN-APP amyloid hypothesis as the leading pathogenesis of Alzheimer's disease (AD). Thus far, 276 missense variants from PSEN1, 2, and APP have been identified. Herein, we report the abilities of variant effect predictors (VEPs) for identifying the degree of pathogenicity among alleles linked with EOAD.
METHODS: We performed pairwise correlations between 276 in vitro functional assays of missense variants from PSEN1, PSEN2, and APP and clinical data among EOAD patients against 37 VEPs. Furthermore, we used the predicted biophysical data of all three proteins to refine our understanding of the molecular basis of missense variants in dominant negative (DN) or loss-of-function (LoF) effects.
RESULTS: We found that VEPs were consistently correlated with age at onset (AAO) among EOAD patients and the amyloid-β (Aβ) 42/Aβ40 ratio biomarker. Regarding the ratio, we observed discrepancies in the predictor variables influencing the Aβ42/Aβ40 ratio, with conflicting evidence as to whether the elevated ratio stems from diminished Aβ40 levels or augmented Aβ42 production. We also identified that with increased predicted pathogenicity, there were decreased Aβ38 levels. Conversely, this study found no direct correlations with Aβ37 and Aβ43. Lastly, structural studies show characteristics of both DN and LoF mechanisms, as there are variants positioned in buried hydrophobic domains and charged surfaces.
DISCUSSION: Currently, a major clinical challenge in the field is the lack of reliable approaches for predicting the pathogenicity of variants in EOAD. Our study also illuminates the need for experimental studies to identify the predictor variable causing the increased Aβ42/Aβ40 biomarker.
HIGHLIGHTS: We performed correlations of 37 VEPs against in vitro data of EOAD variants.VEPs demonstrate potential as diagnostic tools for early onset Alzheimer's disease.Pathogenic missense variants show characteristics of DN and LoF effects.