Origin of the PSEN1 E280A mutation causing early‐onset Alzheimer's disease
Open accessAbstract
Background: A mutation in presenilin 1 (E280A) causes early‐onset Alzheimer's disease. Understanding the origin of this mutation will inform medical genetics. Methods: We sequenced the genomes of 102 individuals from Antioquia, Colombia. We applied identity‐by‐descent analysis to identify regions of common ancestry. We estimated the age of the E280A mutation and the local ancestry of the haplotype harboring this mutation. Results: All affected individuals share a minimal haplotype of 1.8 Mb containing E280A. We estimate a time to most recent common ancestor of E280A of 10 (95% credible interval, 7.2–12.6) generations. We date the de novo mutation event to 15 (95% credible interval, 11–25) generations ago. We infer a western European geographic origin of the shared haplotype. Conclusions: The age and geographic origin of E280A are consistent with a single founder dating from the time of the Spanish Conquistadors who began colonizing Colombia during the early 16th century.
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Colombia has the largest and most homogeneous family group known to have an early-onset (~35 years of age) form of FAD caused by the autosomal dominant and fully penetrant E280A mutation in PSEN1.
“Interestingly, Colombia has the largest and most homogeneous family group known to have an early‐onset (~35 years of age) form of FAD [54, 59] caused by the autosomal dominant and fully penetrant E280A mutation in PSEN1 [60, 61], which generally produces a more aggressive course of pathology than SAD [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [61]
Other genetic variants identified as modifiers or protective against familial Alzheimer's disease (FAD) delay Alzheimer's disease (AD) onset and are related to astrocyte genes, ubiquitin-proteasome function, and p-tau degradation.
“Other genetic variants that have also been identified as modifiers or protective against FAD, delay AD‐onset and are related to astrocyte genes, ubiquitin‐proteasome function, and p‐tau degradation [61, 126, 129]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [61]
The Discussion (page unavailable) says that future ancestry analysis may reveal additional variants influencing disease, but it does not identify protective modifiers or report delayed onset. Searches for astrocyte genes, ubiquitin-proteasome function, p-tau degradation, and age-at-onset modifiers found no passage addressing those claims. (LLM, conf=0.76)
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References 26 · Cited by 60
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- Authors
- Lalli, M. A., Cox, H. C., Arcila, M. L., Cadavid, L., Moreno, S., Garcia, G., Madrigal, L., Reiman, E. M., Arcos‐Burgos, M., Bedoya, G., Brunkow, M. E., Glusman, G., Roach, J. C., Hood, L., Kosik, K. S., & Lopera, F.
- Affiliations
- University of California, Santa Barbara (US)
- Institute for Systems Biology (US)
- Universidad de Antioquia (CO)
- Grupo de Neurociencias de, Antioquia, Universidad de Antioquia Medellín Colombia
- Banner Alzheimer’s Institute (US)
- Australian National University (AU)
- Corresponding author
- Kosik, Kenneth S.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2013-11-18
- Volume
- 10
- Issue
- 5S
- Pages
- S277-S283.e10
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC4019728
- OpenAlex
- W1972028678
- Cited by
- 60
- References
- 26
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 7 · 2014: 2
- FWCI
- 2.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repository University of Antioquia (University of Antioquia) (acceptedVersion, cc-by-nc-nd)
- ANU Open Research (Australian National University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion)
- Funders
- Errett Fisher Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- PSEN1 E280A mutation, early-onset Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Colombia, Haplotypes, Humans, Mutation, Age of Onset, Founder Effect, Genetic Predisposition to Disease, Inheritance Patterns, White People, Presenilin-1
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