Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers

J Alzheimers Dis. 2018;66(2):639-652. doi: 10.3233/JAD-180512.


Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Keywords: Alzheimer’s disease; European multicenter study; cerebrospinal fluid biomarkers; endophenotypes; quantitative trait loci.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoproteins E / genetics
  • Biomarkers / cerebrospinal fluid*
  • Cytoskeletal Proteins / genetics
  • Female
  • Genetic Variation / genetics*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Peptide Fragments / cerebrospinal fluid
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics
  • Phosphorylation / genetics
  • Quantitative Trait Loci
  • tau Proteins / cerebrospinal fluid


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Biomarkers
  • CASS4 protein, human
  • CD2-associated protein
  • Cytoskeletal Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • INPP5D protein, human
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases