Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers

Matthew A. Lalli, Gloria Garcia, Lucia Madrigal, Mauricio Arcos-Burgos, Mary Luz Arcila, Kenneth S. Kosik, Francisco Lopera

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease.

Original languageEnglish
Pages (from-to)1630-1634
Number of pages5
JournalHuman Mutation
Issue number12
StatePublished - Dec 2012
Externally publishedYes


  • Age at onset
  • Alzheimer disease
  • Identity by descent
  • Whole-genome sequencing


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