@article{dcba6fc1cdca4cae9c06241d53e850bb,
title = "Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer{\textquoteright}s disease",
abstract = "Tau deposition is one of two hallmark features of biologically defined Alzheimer{\textquoteright}s disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case–control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.",
keywords = "Alzheimer{\textquoteright}s disease (AD), Amyloid, Cognitive decline, Endophenotype, Polygenic risk score, Tau positron emission tomography (tau PET)",
author = "Ramanan, {Vijay K.} and Heckman, {Michael G.} and Lesnick, {Timothy G.} and Przybelski, {Scott A.} and Cahn, {Elliot J.} and Kosel, {Matthew L.} and Murray, {Melissa E.} and Mielke, {Michelle M.} and Hugo Botha and Jonathan Graff-Radford and Jones, {David T.} and Lowe, {Val J.} and Machulda, {Mary M.} and Jack, {Clifford R.} and Knopman, {David S.} and Petersen, {Ronald C.} and Ross, {Owen A.} and Prashanthi Vemuri",
note = "Funding Information: This work was supported by NIH grants U01 AG006786 (PI: Petersen/Mielke/Jack), R01 NS097495 (PI: Vemuri), R01 AG56366 (PI: Vemuri), P50 AG016574 (PI: Petersen), P30 AG062677 (PI: Petersen), R37 AG011378 (PI: Jack), R01 AG041851 (PIs: Jack and Knopman), R01 AG054449 (PI: Murray), RF1 AG55151 (PI: Mielke), U54 NS100693 (PI: Ross), and R01 AG034676 (PI: Rocca); the GHR Foundation, the Alexander Family Alzheimer{\textquoteright}s Disease Research Professorship of the Mayo Clinic, the Alzheimer{\textquoteright}s Association, the Mayo Foundation for Medical Education and Research, the Liston Award, the Elsie and Marvin Dekelboum Family Foundation, the Schuler Foundation, and Opus Building NIH grant C06 RR018898. We would like to greatly thank AVID Radiopharmaceuticals, Inc., for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: Dr. Vemuri received speaker fees from Miller Medical Communications, Inc. and receives research support from the NIH. Dr. Graff-Radford serves as an assistant editor for Neurology and receives research support from the NIH. Dr. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH. Dr. Murray served as a consultant for AVID Radiopharmaceuticals. Dr. Mielke serves as a consultant for Biogen and Brain Protection Company and receives research funds from the NIH and DOD. Dr. Machulda receives research support from NIH. Dr. Petersen serves as a consultant for Roche Inc., Merck Inc., and Biogen, Inc., serves on the Data Safety Monitoring Board for Genentech, Inc., and receives a royalty from Oxford University Press and UpToDate. Dr. Knopman serves on a Data Safety Monitoring Board for the DIAN study, serves on a Data Safety Monitoring Board for Biogen but receives no personal compensation, is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, and serves as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation. Dr. Jack serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer{\textquoteright}s Disease Research Professorship of the Mayo Clinic. The remaining authors report no relevant financial disclosures. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
year = "2022",
month = may,
doi = "10.1007/s00401-022-02419-2",
language = "English (US)",
volume = "143",
pages = "571--583",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "5",
}