Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.