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

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-beta 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-beta/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.