Basic Science and Pathogenesis

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is analyzing the genetic etiology of early onset (40-64 years) cognitive impairment, including amyloid-positive early-onset Alzheimer's disease (EOAD) and amyloid-negative early-onset Alzheimer's disease (EOnonAD). One goal of this investigation is to identify novel or under-characterized genetic variants. Cognitively impaired (CI) LEADS participants, including amyloid-positive and amyloid-negative early-onset cases, were whole exome or genome sequenced (N = 361). Genetic and copy number variants in APP, PSEN1, PSEN2, GRN, MAPT and C9ORF72 were assessed. Variants in these genes were annotated with Annovar and assessed for potential pathogenicity with criteria including 1,000 genomes population frequency, computational functional prediction, and reported disease occurrence in databases including ClinVar and the Human Gene Mutation Database. Variants were reviewed manually as well as with VarSome and evaluated for pathogenicity using the American College of Medical Genetics criteria. Patient information for carriers of likely pathogenic variants not reported as pathogenic in ClinVar or included in the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU) Trial Eligible list were reviewed. Three CI participants were found to carry the p.I227L variant in PSEN1 (3/361, 1%), with no other pathogenic variants identified in these individuals in the six genes analyzed. This variant was previously described in a single individual. It is classified as likely pathogenic by Varsome based on In-Silico predictors; however, it is listed as "Pathogenicity Not Classified" in AlzForum and as a Variant of Unknown Significance in ClinVar due to the lack of reported cases. The variant is not included in the DIAN-TU Trial Eligible List. We describe the family history, demographic and clinical data for these three participants. The PSEN1 variant p.I227L was identified in three LEADS CI participants and warrants further investigation as a potentially pathogenic variant.