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

DIAN/DIAN-TU Clinical/Genetics Committee, the LEADS Consortium

Research output: Contribution to journalReview articlepeer-review


Introduction: One 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. Methods: LEADS 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. Results: Previously 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. Discussion: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. Highlights: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Original languageEnglish
Pages (from-to)S64-S73
JournalAlzheimer's and Dementia
Issue numberS9
StatePublished - Nov 2023


  • APP
  • Alzheimer's disease
  • C9ORF7
  • GRN
  • MAPT
  • PSEN1
  • PSEN2
  • dementia
  • early onset
  • genetics
  • sequencing


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