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Cited by 128Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease

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Cruchaga, Carlos, Kauwe, John S. K., Mayo, Kevin, Spiegel, Noah, Bertelsen, Sarah, Nowotny, Petra, Shah, Aarti R., Abraham, Richard +14 more·2010·PLoS Genetics
DOI 10.1371/journal.pgen.1001101PMC PMC2940763
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Abstract

Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.

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Authors
Cruchaga, C., Kauwe, J. S. K., Mayo, K., Spiegel, N., Bertelsen, S., Nowotny, P., Shah, A. R., Abraham, R., Hollingworth, P., Harold, D., Owen, M. M., Williams, J., Lovestone, S., Peskind, E. R., Li, G., Leverenz, J. B., Galasko, D., Initiative, T. A. D. N., Morris, J. C., Fagan, A. M., Holtzman, D. M., & Goate, A. M.
Affiliations
  • Washington University in St. Louis (US)
  • Brigham Young University (US)
  • University of Washington (US)
  • Cardiff University (GB)
  • King's College London (GB)
  • University of California San Diego (US)
Corresponding author
Cruchaga, Carlos
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2010-09-16
Volume
6
Issue
9
Pages
e1001101
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1001101
PMC
PMC2940763
OpenAlex
W1992994281
Cited by
128
References
8
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 5 · 2017: 3 · 2016: 10 · 2015: 5 · 2014: 10 · 2013: 20 · 2012: 11
FWCI
9.75
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • Foundation for the National Institutes of Health (P01AG026276, U01AG024904, AG024904)
  • U.S. Department of Veterans Affairs (U01 AG024904)
  • Alzheimer's Association (U01 AG024904)
  • Bristol-Myers Squibb (U01 AG024904, AG024904)
  • Eli Lilly and Company (U01 AG024904, AG024904)
  • Pfizer (AG024904, U01 AG024904)
  • AstraZeneca
  • GlaxoSmithKline (P01AG026276, P01AG03991)
  • Alzheimer's Disease Neuroimaging Initiative (P01AG026276, U01AG024904, AG024904, P01AG03991, P50AG05681)
  • Foundation for Barnes-Jewish Hospital
  • Novartis Pharmaceuticals Corporation (U01 AG024904, AG024904)
  • Northern California Institute for Research and Education (U01 AG024904)
  • Elan (U01 AG024904)
  • Eisai (U01 AG024904, AG024904)
  • National Institutes of Health (5u01ag024904-10, U01-AG024904, AG024904, AG05136)
  • U.S. Food and Drug Administration
  • University of California, Los Angeles
  • University of California, San Diego
  • National Institute on Aging (U01-AG-024904, AG 16208, AG 05136, AG 024904, P50AG005681, P01AG003991, R01AG023185, P50AG005136, U19AG010483, R01AG016208, P01AG026276)
  • National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
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, p-tau181, endophenotypes, disease progression rate, PP2A regulatory subunit, genetic risk factors, cognitive decline, APOE ε4, amyloid-beta 42
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Peptide Fragments, Phosphoproteins, Risk Factors, RNA, Messenger, Washington, Reproducibility of Results, Biomarkers, Survival Analysis, Amyloid beta-Peptides, tau Proteins, Age of Onset, Disease Progression, Calcineurin, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide

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