4.6 Article

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease

期刊

ACTA NEUROPATHOLOGICA
卷 143, 期 5, 页码 571-583

出版社

SPRINGER
DOI: 10.1007/s00401-022-02419-2

关键词

Alzheimer's disease (AD); Amyloid; Cognitive decline; Endophenotype; Polygenic risk score; Tau positron emission tomography (tau PET)

资金

  1. NIH [U01 AG006786, R01 NS097495, R01 AG56366, P50 AG016574, P30 AG062677, R37 AG011378, R01 AG041851, R01 AG054449, RF1 AG55151, U54 NS100693, R01 AG034676]
  2. GHR Foundation
  3. Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic
  4. Alzheimer's Association
  5. Mayo Foundation for Medical Education and Research
  6. Elsie and Marvin Dekelboum Family Foundation
  7. Schuler Foundation
  8. Opus Building NIH [C06 RR018898]
  9. AVID Radiopharmaceuticals, Inc. [AV-1451]
  10. Liston Award

向作者/读者索取更多资源

This study found that a polygenic risk score (PRS) based on tau PET can effectively capture tau deposition levels and genetic background influencing tau accumulation. It outperformed amyloid PET burden and APOE ε4 in capturing tau deposition. The tau PRS was also associated with cerebrospinal fluid phosphorylated tau levels and postmortem neurofibrillary tangle stage. Additionally, it showed an interaction with amyloid burden on cognitive decline.
Tau deposition is one of two hallmark features of biologically defined Alzheimer'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-beta 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) epsilon 4 (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.

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