d-serine levels in Alzheimer's disease: implications for novel biomarker development

Transl Psychiatry. 2015 May 5;5(5):e561. doi: 10.1038/tp.2015.52.


Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Biomarkers / cerebrospinal fluid
  • Biomarkers / metabolism*
  • Case-Control Studies
  • Cerebral Cortex / metabolism*
  • Depressive Disorder, Major / cerebrospinal fluid
  • Disease Models, Animal
  • Female
  • Hippocampus / metabolism*
  • Humans
  • Hydrocephalus, Normal Pressure / cerebrospinal fluid
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Rats
  • Serine


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Biomarkers
  • Serine