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-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.