APOE and other loci affect age‐at‐onset in Alzheimer's disease families with PS2 mutation
Abstract
Several kindreds of Volga German (VG) ancestry have a single PS2 mutation that causes an autosomal dominant form of Alzheimer's disease (AD). These families show a wide range in age‐at‐onset, which suggests the existence of modifying factors other than the PS2 mutation. To examine evidence for a genetic basis of variation in onset age, we performed a Bayesian oligogenic segregation and linkage analysis on nine VG families confirmed to have at least one affected PS2 carrier. This analysis simultaneously estimated the effects of APOE and PS2 and the number and effects of additional loci affecting AD age‐at‐onset. In addition, a family effect accounted for shared environmental effects. This analysis approach has the advantage of full use of the complete pedigree structure, as well as use of information on unsampled individuals with phenotypic data. These analyses provide evidence that APOE plays a small, but significant, role in modifying the age‐at‐onset in these VG families. The effects estimated for the APOE ε3 and ε4 genotypes were consistent with those estimated in previous analysis of late‐onset AD families, with evidence for a dose‐dependent relationship between number of ε4 alleles and age‐at‐onset. We estimated an ∼83% posterior probability of at least one modifier locus in addition to APOE, and that the fraction of the variance in age‐at‐onset attributable to PS2, APOE, other loci, and family effects is ∼70, ∼2, ∼6.5, and ∼8.5%, respectively. These results provide evidence that APOE and other loci modify onset in AD caused by PS2 mutation. © 2004 Wiley‐Liss, Inc.
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In autosomal dominant AD, onset age tends to be similar across generations and is influenced mainly by the mutation and family genetic background.
“The age at clinical onset of autosomal dominant Alzheimer’s disease is similar between generations14 and is affected mostly by the mutation type and background family genetics.15”
From Clinical and biomarker changes in dominantly inherited Alzheimer's disease (2012) · cites this paper as [15]
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- Authors
- Wijsman, E. M., Daw, E. W., Yu, X., Steinbart, E. J., Nochlin, D., Bird, T. D., & Schellenberg, G. D.
- Affiliations
- University of Washington (US)
- Harborview Medical Center (US)
- Corresponding author
- Wijsman, Ellen M.
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2004-09-23
- Volume
- 132B
- Issue
- 1
- Pages
- 14-20
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W2163362744
- Cited by
- 79
- References
- 50
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 7
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG021544, AG 05136, AG21544, AG11762, P50AG005136, U24AG021886)
- National Institute of General Medical Sciences (GM46255)
- 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
- Alzheimer's disease, age of onset, apolipoprotein E, modifier loci, autosomal dominant Alzheimer's disease, family impact, APOE ε4, dose-dependent effects, genetic heterogeneity
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Apolipoproteins E, Bayes Theorem, Chromosomes, Human, Pair 1, Family Health, Female, Genotype, Humans, Genetic Linkage, Male, Membrane Proteins, Middle Aged, Mutation, Pedigree, Age of Onset, Microsatellite Repeats, Genetic Predisposition to Disease, Quantitative Trait Loci, Presenilin-2
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