Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers
Open accessAbstract
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.
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Whole-genome sequencing approaches have suggested some rare variants as potential modifiers of age of onset in the E280A pedigree.
“Other approaches using whole-genome sequencing have suggested some rare variants as potential modifiers of the ADAOO in this pedigree.5”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [5]
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References 39 · Cited by 19
- Authors
- Lalli, M. A., Garcia, G., Madrigal, L., Arcos-Burgos, M., Arcila, M. L., Kosik, K. S., & Lopera, F.
- Affiliations
- University of California, Santa Barbara (US)
- Universidad de Antioquia (CO)
- Corresponding author
- Kosik, Kenneth S.
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2012-08-10
- Volume
- 33
- Issue
- 12
- Pages
- 1630-1634
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC3496074
- OpenAlex
- W2078571392
- Cited by
- 19
- References
- 39
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2016: 1 · 2015: 5 · 2013: 1 · 2012: 1
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Errett Fisher Foundation
- Universidad de Antioquia
- National Institutes of Health
- National Institute on Aging (R21AG024063, R01AG029802)
- Fogarty International Center
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- familial Alzheimer's disease, age of onset, presenilin 1, genetic variants, identity by descent, whole genome sequencing, autosomal dominant inheritance
- MeSH terms
- Age Factors, Alzheimer Disease, Chromosome Mapping, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 16, Gene Frequency, Humans, Genome, Human, Open Reading Frames, Sequence Analysis, DNA, Mutation, Missense, Genetic Association Studies
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