Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis

Nat Genet. 2021 Feb;53(2):143-146. doi: 10.1038/s41588-020-00773-z. Epub 2021 Jan 28.


Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Apolipoproteins E / genetics
  • Brain / metabolism*
  • Epoxide Hydrolases / genetics
  • Genome-Wide Association Study
  • Humans
  • Parkinson Disease / genetics
  • Polymorphism, Single Nucleotide
  • Proteome / genetics*
  • Quantitative Trait Loci
  • Receptors, Virus / genetics
  • Sequence Analysis, RNA
  • Single-Cell Analysis


  • ApoE protein, human
  • Apolipoproteins E
  • Proteome
  • Receptors, Virus
  • poliovirus receptor
  • Epoxide Hydrolases
  • EPHX2 protein, human