Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort

IntroductionOne goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.MethodsLEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.ResultsPreviously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.DiscussionResults suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.

Automated summary

The Longitudinal Early-onset Alzheimer's Disease Study aims to investigate the genetic causes of early onset cognitive impairment. The study found that the participants had a low frequency of common pathogenic variants.