Abstract
BackgroundIdeally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.Methods and FindingsCSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively.ConclusionsFour novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.
Highlights
Clinicopathological studies suggest that Alzheimer’s disease (AD) pathology begins 10–15 years before the onset of very mild dementia [1,2]
Four novel cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of amyloid beta 42 peptide (Ab42) and tau. These six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline
Our findings suggest that a small ensemble of novel biomarkers may be able to distinguish several stages of cognitive decline in early AD, and improve the ability of current leading biomarkers tau and Ab42 to discriminate early symptomatic AD from cognitive normalcy
Summary
Clinicopathological studies suggest that Alzheimer’s disease (AD) pathology (amyloid plaque formation, followed by gliosis and neurofibrillary tangle formation) begins 10–15 years before the onset of very mild dementia [1,2] This period of ‘preclinical AD’ could provide an opportunity for disease modifying therapies to prevent or forestall the synaptic and neuronal losses associated with cognitive impairment [3,4,5]. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome
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