Alzheimers Dement. 2021 Dec;17 Suppl 3:e056493. doi: 10.1002/alz.056493.
BACKGROUND: The Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) aims to enroll and study participants with sporadic early-onset Alzheimer’s disease (EOAD) or early-onset non-Alzheimer’s dementia (EOnonAD). Study exclusion criteria include having two or more first degree relatives with early-onset dementia in absence of genetic screening. LEADS conducts genetic screening for EOAD/EOnonAD participants to identify those with known pathogenic mutations and disenroll subjects eligible for the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD), and to prioritize EOAD/EOnonAD without known mutations for follow up and participation in clinical trials.
METHOD: Five genes were screened for known pathogenic mutations, amyloid beta precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), granulin precursor (GRN), and microtubule associated protein tau (MAPT). Participants were also screened for repeat expansion in C9orf72-SMCR8 complex subunit (C9orf72). Pathogenic mutations for GRN and MAPT were curated from the Human Gene Mutation Database (HGMD), ClinVar, and the Leiden Open Variation Database. Pathogenic mutations for APP, PSEN1, and PSEN2 were obtained from the DIAN-TU Trial Eligible List. Whole exome sequencing (WES) was performed at the Center for Medical Genomics at Indiana University School of Medicine, and processed using GenomeAnalysisToolkit (GATK) best practices. C9orf72 repeat expansion was tested for using repeat primed PCR at the Emory Center for Neurodegenerative Disease.
RESULTS: Of the 150 participants screened for mutations and 144 screened for C9orf72 repeat expansion, three individuals with pathogenic mutations (one heterozygous for PSEN1, c.487C>T, p.His163Tyr; one heterozygous for GRN c.933+1G>C; and one heterozygous for GRN c.1145delC, p.Thr382Serfs*30) and one C9orf72 pathogenic repeat expansion were identified. Mutation carriers were White non-Hispanic with age-at-onset between 55 and 58 years, Clinical Dementia Rating (CDR) scale global score of 0.5 or 1, and Mini-Mental State Examination (MMSE) score between 25-28. Two mutation carriers had Apolipoprotein E (APOE) genotypes of ε3/ε3, while two were ε3/ε4.
CONCLUSION: Strict adherence to the current LEADS inclusion/exclusion criteria assures that most cognitively impaired LEADS participants do not have a known pathogenic mutation, and that this cohort may be enriched for novel early-onset dementia-related pathogenic mutations.