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

Alzheimers Dement. 2023 Nov;19 Suppl 9(Suppl 9):S64-S73. doi: 10.1002/alz.13482. Epub 2023 Oct 6.


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.

Keywords: APP; Alzheimer's disease; C9ORF7; GRN; MAPT; PSEN1; PSEN2; dementia; early onset; genetics; sequencing.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / genetics
  • Amyloid beta-Protein Precursor / genetics
  • C9orf72 Protein / genetics
  • Genetic Testing
  • Humans
  • Longitudinal Studies
  • Mutation
  • Presenilin-1 / genetics
  • Presenilin-2 / genetics


  • Amyloid beta-Protein Precursor
  • C9orf72 Protein
  • Presenilin-1
  • Presenilin-2

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