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

Abstract

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.

Keywords: Alzheimer’s disease; NRG1; Plasma biomarker; Synaptic pathology.

Fig. 1

Plasma NRG1 levels across groups and correlation to CSF NRG1. A Box plots displaying plasma NRG1 levels across diagnosis groups. Levels were compared using a one-way ANCOVA adjusted on age and sex followed by a post hoc LSD test adjusted for multiple comparisons. B Box plot displaying plasma NRG1 levels in Aβ-positive patients (n = 62) and Aβ-negative patients (n = 55). Levels were compared using a one-way ANCOVA adjusted on age and sex followed by a post hoc LSD test adjusted for multiple comparisons. C ROC curves displaying plasma NRG1 accuracy in differentiating AD patients from neurological controls (AUC = 87.6%, 95% CI: 76.9–98.2%), AD dementia from non-AD dementia patients (AUC = 69.3%, 95% CI: 55.7– 82.3%), AD-MCI from NC (AUC = 88.3%, 95% CI: 77.2–0.99.6%), and AD-MCI from non-AD MCI patients (AUC = 86.4%, 95% CI: 74.7–98.3%). Abbreviations: Aβ, amyloid-beta; AD, Alzheimer’s disease; AUC, area under the curve; MCI mild cognitive impairment; LSD test, least square difference test; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NRG1, neuregulin 1; ROC, receiver operator characteristics

Fig. 2

Association to AD CSF biomarkers. Association of plasma NRG1 with A CSF NRG1 B CSF Aβ42/Aβ40 ratio, C CSF p-tau, and D CSF t-tau, studied using linear regression adjusted on age and sex, in the whole cohort and in regard to Aβ status. Solid lines indicate the regression line and dashed lines, the 95% CI in Aβ-positive and Aβ-negative groups. Abbreviations: Aβ+, amyloid-beta positive; Aβ-, amyloid-beta negative; Aβ42, β-amyloid 42; Aβ40, β-amyloid 40; AD, Alzheimer’s disease; 95% CI, confidence interval; CSF, cerebrospinal fluid; NRG1, neuregulin 1; p-tau, phosphorylated tau; t-tau, total tau

Fig. 3

Association to CSF synaptic biomarkers and cognition. Association of plasma NRG1 with A CSF GAP-43, B CSF neurogranin, C CSF SNAP-25, and D MMSE, studied using linear regression adjusted on age and sex, in the whole cohort and in regard to Aβ status. Solid lines indicate the regression line and dashed lines, the 95% CI in Aβ-positive and Aβ-negative groups. Abbreviations: Aβ+, amyloid-beta positive; Aβ-, amyloid-beta negative; 95% CI, 95% confidence interval; CSF, cerebrospinal fluid; GAP-43, growth-associated protein 43; MMSE, Mini-Mental State Examination; NRG1, neuregulin 1; SNAP-25, synaptosomal associated protein 25