Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease
Open accessAbstract
BACKGROUND: Heritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses. METHODS: We genotyped 75 variants in our cohort and, using a two-staged study design, we developed a 17-marker AD risk score in a Discovery cohort (n = 59 cases, n = 133 controls) then assessed its utility in a second Validation cohort (n = 126 cases, n = 150 controls). We also performed a data-driven decision tree analysis to identify genetic and/or demographic criteria that are most useful for accurately differentiating all AD cases from controls. RESULTS: We confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort. In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD. In AtAD, HFE SNP rs1799945 was the strongest predictor of disease; variation in HFE has previously been implicated in AD risk in non-ε4 carriers. CONCLUSIONS: Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.
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PRS incorporating only genome-wide significant SNPs show only a modest improvement in disease prediction over known risk factors such as APOEε4, age, and sex.
“PRS incorporating only genome-wide significant SNPs have showed only a modest improvement in disease prediction over known risk factors such as APOEε4, age, and sex [119–121].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [121]
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Self-citationA mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
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Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease
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Who is at risk for dropout from group cognitive-behavior therapy for insomnia?
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Genetic architecture of Alzheimer's disease
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“PRS incorporating only genome-wide significant SNPs have showed only a modest improvement in disease prediction over known risk factors such as APOE ε4, age, and sex (Sleegers et al., 2015; Chouraki et al., 2016; Yokoyama et al., 2015).”
Method
- Authors
- Yokoyama, J. S., Bonham, L. W., Sears, R. L., Klein, E., Karydas, A., Kramer, J. H., Miller, B. L., & Coppola, G.
- Affiliations
- University of California, San Francisco (US)
- University of California, Los Angeles (US)
- Corresponding author
- Yokoyama, Jennifer S
- ORCID
- Venue
- BMC Neurology
- Published
- 2015-03-28
- Volume
- 15
- Issue
- 1
- Pages
- 47-47
- ISSN
- 1471-2377 (ISSN-L)
- PMC
- PMC4459447
- OpenAlex
- W2032447992
- Cited by
- 28
- References
- 8
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Larry L. Hillblom Foundation (2012‐A‐015‐FEL)
- John Douglas French Alzheimer's Foundation
- National Institutes of Health (AG023501)
- National Institute on Aging (RC1AG035610, R01 AG26938, K01AG049152, U24 AG21886, AG023501, R01AG026938, P01AG019724, U24AG021886, P50AG023501)
- National Institute of Neurological Disorders and Stroke (P30NS062691, NS062691, U24 AG21886)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, genetic risk, APOE ε4, atypical Alzheimer's disease, amnestic Alzheimer's disease, polygenic risk score, decision tree analysis, phenotypic heterogeneity, sporadic Alzheimer's disease, genetic risk prediction
- MeSH terms
- Aged, Aged, 80 and over, Algorithms, Alleles, Alzheimer Disease, Decision Trees, Female, Genetic Markers, Genotype, Humans, Male, Neurologic Examination, Phenotype, Risk Factors, Cohort Studies, Risk Assessment, Apolipoprotein E4
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