Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study

Abstract

Background The discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology. Methods We examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD‐symptomatic (DSAD) and AD‐asymptomatic (aDS) individuals with DS, as well as controls (HC). Results ProNGF and MMP‐3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP‐3, and MMP‐9. ProNGF and MMP‐9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex. Discussion Brain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS.

Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

“…In a later study that quantified the levels of several NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator (tPA), and metalloproteases) in samples from AD-asymptomatic DS (n = 14), prodromal AD (n = 10) DS, AD dementia (n = 12), and controls (n = 16), ProNGF and MMP-3 levels were elevated, while tPA was decreased in plasma in individuals with DS. The plasma levels of neuroserpin and MMP-9 were similar between all groups [116].…”

Nerve Growth Factor Compromise in Down Syndrome

“…Analysis of NGF pathway proteins in matched CSF/plasma samples from DSAD and individuals with DS aDS, as well as controls, revealed that the levels of the 50 kDa isoform of proNGF and MMP9 in CSF were competent to identify symptomatic AD from the wider DS population. Both members of the NGF metabolic pathway identified symptomatic AD from the wider DS population with a sensitivity and specificity matching or outperforming that of the classical AD CSF biomarkers pTau, tTau, and the AB42/40 ratio ( Pentz et al, 2021a ). Importantly, longitudinal increases in 50 kDa proNGF levels in plasma over 1 year correlated to prospective cognitive decline over the subsequent 2 years ( Iulita and Cuello, 2016 ), demonstrating a potential value of NGF-related biomarkers in identifying incipient cognitive decline in this population.…”

“…Several studies have demonstrated that changes in plasma Aβ40 and Aβ42 in DS correlate with AD onset ( Schupf et al, 2007 ; Jones et al, 2009 ; Matsuoka et al, 2009 ; Schupf et al, 2010 ; Coppus et al, 2012 ). As for Tau, increases in CSF total Tau (tTau) and phosphorylated Tau (pTau), have been correlated with AD onset in DS ( McGlinchey et al, 2020 ; Pentz et al, 2021a ). Likewise, plasma neurofilament light (NfL), and IL1β, have been shown in multiple studies to reliably distinguish DSAD individuals with DS asymptomatic for AD (aDS) ( Petersen and O’Bryant, 2019 ; Startin et al, 2019 ; McGlinchey et al, 2020 ).…”

“…Given that degeneration of the cortical forebrain cholinergic system is a critical factor associated with cognitive decline in AD, both in the general population and in DS, as discussed above, current AD biomarker panels should be enriched by the addition of biomarkers able to monitor cholinergic dysfunction in both research and clinical contexts ( Hampel et al, 2018 ; Cuello et al, 2019 ; Pentz et al, 2021a ). NGF dysmetabolism’s presence within DS and AD brains, and its relationship to cholinergic dysfunction, present the opportunity for the identification of novel biomarkers signifying AD pathology and subtyping for cholinergic dysfunction within DS populations.…”

Integrative Functional Genomic Analysis of Molecular Signatures and Mechanistic Pathways in the Cell Cycle Underlying Alzheimer’s Disease

“…Progress in the cell cycle depends on the coordination and interaction of trophic factors with two categories of regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs) [11,12]. For instance, nerve growth factor (NGF) inhibits the induction of cyclins and their associations with specific CDKs, hence interrupting cell cycle reentry through the G1-phase [13]. Insulin-like growth factor 1 (IGF-1) prevents the expression of cell cycle proteins (e.g., cyclin A, D1, and CDK2) known to stimulate G1 quiescent cells to enter the S-phase [14].…”