Degree of genetic liability for Alzheimer's disease associated with specific proteomic profiles in cerebrospinal fluid

Neurobiol Aging. 2020 Sep:93:144.e1-144.e15. doi: 10.1016/j.neurobiolaging.2020.03.012. Epub 2020 Mar 24.

Abstract

Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD.

Keywords: Alzheimer's disease (AD); Cell adhesion molecules; Cerebrospinal fluid (CSF); Complement cascades; Cytokines; Polygenic risk scores (PGRS).

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*
  • Amyloid Precursor Protein Secretases / cerebrospinal fluid
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Chitinase-3-Like Protein 1 / cerebrospinal fluid*
  • Cognitive Dysfunction / genetics
  • Female
  • Genetic Association Studies*
  • Humans
  • Male
  • Peptide Fragments / cerebrospinal fluid*
  • Polymorphism, Single Nucleotide
  • Proteomics*
  • Risk
  • Young Adult
  • alpha-Synuclein / cerebrospinal fluid*
  • tau Proteins / cerebrospinal fluid*

Substances

  • Amyloid beta-Peptides
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • Peptide Fragments
  • alpha-Synuclein
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Amyloid Precursor Protein Secretases