A genetics-based biomarker risk algorithm for predicting risk of Alzheimer's disease
Open accessAbstract
Introduction: A straightforward, reproducible blood‐based test that predicts age‐dependent risk of Alzheimer's disease (AD) could be used as an enrichment tool for clinical development of therapies. This study evaluated the prognostic performance of a genetics‐based biomarker risk algorithm (GBRA) established on a combination of apolipoprotein E ( APOE )/translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes and age, then compare it to cerebrospinal fluid (CSF) biomarkers, neuroimaging, and neurocognitive tests using data from two independent AD cohorts. Methods: The GBRA was developed using data from the prospective Joseph and Kathleen Bryan, Alzheimer's Disease Research Center study (n = 407; 86 conversion events [mild cognitive impairment {MCI} or late‐onset Alzheimer's disease {LOAD}]). The performance of the algorithm was tested using data from the Alzheimer's Disease Neuroimaging Initiative study (n = 660; 457 individuals categorized as MCI or LOAD). Results: The positive predictive values and negative predictive values of the GBRA are in the range of 70%–80%. The relatively high odds ratio (approximately 3–5) and significant net reclassification index scores comparing the GBRA to a version based on APOE and age alone support the value of the GBRA in risk prediction for MCI due to LOAD. Performance of the GBRA compares favorably with CSF and imaging (functional magnetic resonance imaging) biomarkers. In addition, the GBRA “high” and “low” AD‐risk categorizations correlated well with pathologic CSF biomarker levels, positron emission tomography amyloid burden, and neurocognitive scores. Discussion: Unlike dynamic markers (i.e., imaging, protein, or lipid markers) that may be influenced by factors unrelated to disease, genomic DNA is easily collected, stable, and the technical methods for measurement are robust, inexpensive, and widely available. The performance characteristics of the GBRA support its use as a pharmacogenetic enrichment tool for LOAD delay‐of‐onset clinical trials and merit further evaluation for its clinical utility in evaluating therapeutic efficacy.
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Carrying one copy of ApoE4 triples the risk of developing AD, and carrying two copies confers a 90% lifetime risk.
“Possession of one copy of ApoE4 triples the risk of developing AD, while individuals with two copies have a 90% lifetime risk of developing the disease.”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [12]
The ε4 isoform of apolipoprotein E (ApoE4) is a major genetic risk factor for late-onset Alzheimer's disease (AD).
“A major genetic risk factor for late-onset (AD) is the ε4 isoform of apolipoprotein E (ApoE4)”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [12]
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ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
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- Authors
- Lutz, M. W., Sundseth, S. S., Burns, D. K., Saunders, A. M., Hayden, K. M., Burke, J. R., Welsh‐Bohmer, K. A., Roses, A. D., & Initiative, A. D. N.
- Affiliations
- Duke Medical Center (US)
- Cabernet Pharmaceuticals Durham NC USA
- Wolfspeed, Inc. (United States) (US)
- Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center Durham NC USA
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Corresponding author
- Lutz, Michael W.
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2016-01
- Volume
- 2
- Issue
- 1
- Pages
- 30-44
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC4817110
- OpenAlex
- W2258850935
- Cited by
- 30
- References
- 42
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 2
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIA R01 AG040370, NIA P30AG‐028377, NIA R01 AG042633, U01 AG024904)
- U.S. Department of Defense (W81XWH‐12‐2‐0012)
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- BioClinica
- Biogen
- Eli Lilly and Company
- Norman Cousins Center for Psychoneuroimmunology
- Genentech
- GE Healthcare
- H. Lundbeck A/S
- Novartis Pharmaceuticals Corporation
- Pfizer
- Servier
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- Northern California Institute for Research and Education
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- Alzheimer's disease, apolipoprotein E, TOMM40, mild cognitive impairment, late-onset Alzheimer's disease, cerebrospinal fluid biomarkers, neuroimaging biomarkers, clinical trial participant selection, net reclassification improvement
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