Plasma neuregulin 1 as a synaptic biomarker in Alzheimer’s disease: a discovery cohort study

Background Synaptic dysfunction is an early core feature of Alzheimer’s disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. Objective To measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers. Methods This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI, n = 27) and at dementia stage ( n = 35), non-AD dementia ( n = 26, Aβ-negative), non-AD MCI ( n = 19), and neurological controls ( n =20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25. Results Plasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P < 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 ( β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ-positive patients ( β = −0.197–0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 ( β = 0.278–0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ-positive patients (all, β = −0.188, P = 0.038; Aβ+: β = −0.255, P = 0.038). Conclusion Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD.