Heritability of Alzheimer-related plasma biomarkers in the Amish population

  1. Ping Wang
  2. Yeunjoo E. Song
  3. Audrey Lynn
  4. Kristy Miskimen
  5. Alex Gulyayev
  6. Michael B. Prough
  7. Daniel A. Dorfsman
  8. Renee A. Laux
  9. Sarada L. Fuzzell
  10. Sherri D. Hochstetler
  11. Andrew F. Zaman
  12. Larry D. Adams
  13. Laura J. Caywood
  14. Jason E. Clouse
  15. Sharlene D. Herington
  16. Patrice Whitehead
  17. Yining Liu
  18. Noel Moore
  19. Paula Ogrocki
  20. Alan J. Lerner
  21. Anthony J. Griswold
  22. Jeffery M. Vance
  23. Michael L. Cuccaro
  24. William K. Scott
  25. Margaret A. Pericak-Vance
  26. Jonathan L. Haines
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Abstract

INTRODUCTION

Plasma biomarkers for Alzheimer disease (AD) hold promise for disease diagnosis and prediction, yet their genetic underpinnings remain underexplored.

METHODS

We measured plasma amyloid beta 40 (Aβ40), Aβ42, Aβ42/Aβ40, total tau (t-tau), phosphorylated tau 181 (p-tau181), Aβ42/t-tau, Aβ42/p-tau181, neurofilament light chain, and glial fibrillary acidic protein in the Midwestern Amish. Pedigree-based heritability<inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="25327557v2_inline1.gif"/></inline-formula>was estimated from multigenerational pedigrees, and SNP-based heritability<inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="25327557v2_inline2.gif"/></inline-formula>was derived from single nucleotide polymorphisms (SNPs).

RESULTS

Among all Amish individuals, additive genetic effects<inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="25327557v2_inline3.gif"/></inline-formula>explained 11.1% to 36.6% of biomarker variances.<inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="25327557v2_inline4.gif"/></inline-formula>estimates were consistently lower, ranging from 6.7% to 28.7%. The heritability of these biomarkers in subgroups of cognitively normal individuals andAPOEε4 non-carriers yielded similar results.

DISCUSSION

Plasma biomarkers such as amyloid β, t-tau, and p-tau181 are moderately heritable in the Amish, underscoring the impact of genetic determinants of plasma biomarkers associated with AD.

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