Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults

  1. Jaclyn M. Eissman
  2. Alexandra N. Regelson
  3. Skylar Walters
  4. Derek B. Archer
  5. Alaina Durant
  6. Shubhabrata Mukherjee
  7. Michael L. Lee
  8. Seo-Eun Choi
  9. Phoebe Scollard
  10. Emily H. Trittschuh
  11. Jesse Mez
  12. Moonil Kang
  13. William S. Bush
  14. Brian W. Kunkle
  15. Adam C. Naj
  16. Katherine A. Gifford
  17. Murat Bilgel
  18. Amanda B. Kuzma
  19. The Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  20. The Alzheimer’s Disease Genetics Consortium (ADGC)
  21. The Alzheimer’s Disease Sequencing Project (ADSP)
  22. Michael L. Cuccaro
  23. Carlos Cruchaga
  24. Margaret A. Pericak-Vance
  25. Lindsay A. Farrer
  26. Li-San Wang
  27. Gerard D. Schellenberg
  28. Badri N. Vardarajan
  29. Richard Mayeux
  30. Jonathan L. Haines
  31. Angela L. Jefferson
  32. Walter A. Kukull
  33. C. Dirk Keene
  34. Andrew J. Saykin
  35. Paul M. Thompson
  36. Eden R. Martin
  37. Marilyn S. Albert
  38. Sterling C. Johnson
  39. Corinne D. Engelman
  40. Luigi Ferrucci
  41. David A. Bennett
  42. Lisa L. Barnes
  43. Julie A. Schneider
  44. Susan M. Resnick
  45. Reisa A. Sperling
  46. Paul K. Crane
  47. Timothy J. Hohman
  48. Logan Dumitrescu
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Abstract

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer’s disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus,VRK2(rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired,DCHS2(rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning,AGA(rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults.

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