Increased neurogranin concentrations in cerebrospinal fluid of Alzheimer’s disease and in mild cognitive impairment due to AD

Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer’s disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an “AD-like” CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies.