Polygenic risk score of sporadic late‐onset Alzheimer's disease reveals a shared architecture with the familial and early‐onset forms
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Abstract
Objective: To determine whether the extent of overlap of the genetic architecture among the sporadic late‐onset Alzheimer's Disease (sLOAD), familial late‐onset AD (fLOAD), sporadic early‐onset AD (sEOAD), and autosomal dominant early‐onset AD (eADAD). Methods: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome‐wide significant loci for LOAD risk. Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 −7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 −7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 −3 ). The PRS was associated with cerebrospinal fluid ptau 181 ‐Aβ 42 on eADAD ( P = 4.36 × 10 −2 ). Conclusion: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
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GWAS variants were not associated with risk for familial EOAD inherited in an autosomal dominant fashion.
“Although GWAS variants were not associated with risk for familial EOAD inherited in an autosomal dominant fashion, the researchers noted that the sample size was small and that variant burden may have been associated with age at symptom onset in these families [26].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [26]
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References 56 · Cited by 138
- Authors
- Cruchaga, C., Del‐Aguila, J. L., Saef, B., Black, K., Fernandez, M. V., Budde, J., Ibanez, L., Deming, Y., Kapoor, M., Tosto, G., Mayeux, R. P., Holtzman, D. M., Fagan, A. M., Morris, J. C., Bateman, R. J., Goate, A. M., Dominantly Inherited Alzheimer Network (DIAN), (ADNI), D. N. I., study, N. F., & Harari, O.
- Affiliations
- Washington University in St. Louis (US)
- Department of Psychiatry Washington University School of Medicine St. Louis MO USA
- Icahn School of Medicine at Mount Sinai (US)
- NewYork–Presbyterian Hospital (US)
- Pontificia Universidad Católica Madre y Maestra (DO)
- Corresponding author
- Harari, Oscar
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2017-09-21
- Volume
- 14
- Issue
- 2
- Pages
- 205-214
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC5803427
- OpenAlex
- W2739334724
- Cited by
- 138
- References
- 56
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 16 · 2023: 13 · 2022: 16 · 2021: 22 · 2020: 28 · 2019: 13 · 2018: 9 · 2017: 1
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Institute of Clinical and Translational Sciences (UL1TR000448)
- National Institute of Biomedical Imaging and Bioengineering
- National Institute on Aging
- Alzheimer's Disease Neuroimaging Initiative (U01 AG024904)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institutes of Health (P50 AG05681, P01 AG03991, P01 AG026276, R01‐AG044546, P01‐AG003991, RF1AG053303, R01‐AG035083, R01‐NS085419)
- Alzheimer's Association (NIRG‐11‐200110)
- 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, polygenic risk score
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Family Health, Female, Genotype, Humans, Male, Middle Aged, Mutation, Peptide Fragments, ROC Curve, Cohort Studies, Logistic Models, Databases, Bibliographic, Amyloid beta-Peptides, tau Proteins, Age of Onset, Genetic Predisposition to Disease, Multifactorial Inheritance
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