Abstract
BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of cognitive and functional deficits in people with altered Aβ and tau levels. While multiple previous studies identified non-Aβ, non-tau proteins as candidate neurodegenerative markers to inform the A/T/N biomarker scheme of AD, few have advanced beyond association with clinical AD diagnosis. Here we analyzed nine promising neurodegenerative markers in a three-centered cohort using independent assays to identify candidates most likely to complement Aβ and tau in the A/T/N framework.MethodsCSF samples from 125 subjects recruited at the three centers were exchanged such that each of the nine previously identified biomarkers can be measured at one of the three centers. Subjects were classified according to cognitive status and CSF AD biomarker profiles as having normal cognition and normal CSF (n = 31), normal cognition and CSF consistent with AD (n = 13), mild cognitive impairment and normal CSF (n = 13), mild cognitive impairment with CSF consistent with AD (n = 23), AD dementia (n = 32; CSF consistent with AD), and other non-AD dementia (n = 13; CSF not consistent with AD).ResultsThree biomarkers were identified to differ among the AD stages, including neurofilament light chain (NfL; p < 0.001), fatty acid binding protein 3 (Fabp3; p < 0.001), and interleukin (IL)-10 (p = 0.033). Increased NfL levels were most strongly associated with the dementia stage of AD, but increased Fabp3 levels were more sensitive to milder AD stages and correlated with both CSF tau markers. IL-10 levels did not correlate with tau biomarkers, but were associated with rates of longitudinal cognitive decline in mild cognitive impairment due to AD (p = 0.006). Prefreezing centrifugation did not influence measured CSF biomarker levels.ConclusionCSF proteins associated with AD clinical stages and progression can complement Aβ and tau markers to inform neurodegeneration. A validated panel inclusive of multiple biomarker features (etiology, stage, progression) can improve AD phenotyping along the A/T/N framework.
Highlights
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events
This A/T/N framework has the advantage of providing a multidimensional view of AD, accurate antemortem detection of all three features remains an obstacle in early diagnosis and clinical trial design
NANT biomarker assays Nine NANT analytes were selected by WTH, AMF, and SEA for validation based on previous biomarker discovery studies, and assay development and performance took place at Emory University (Emory) (interleukin (IL)-7, IL-10, fractalkine, tumor necrosis factor (TNF)-α), Penn (fatty acid binding protein 3 (Fabp3), insulin-like growth factor binding protein 2 (IGF-BP2), neurofilament light chain (NfL)), and Washington University (WU) (monocyte chemotactic protein 1 (MCP1), chitinase-3-like protein 1 (YKL-40))
Summary
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. The clinicopathologic description of Alzheimer’s disease (AD) underwent recent revisions to better characterize, on parallel continuums, the cognitive and neuropathologic features associated with beta-amyloid (Aβ) deposition, tau hyperphosphorylation, and neurodegeneration [1,2,3,4,5]. This A/T/N framework has the advantage of providing a multidimensional view of AD, accurate antemortem detection of all three features remains an obstacle in early diagnosis and clinical trial design. This may be due to many issues, including recruitment bias [18], processing artifacts when assays are performed by commercial vendors [19], and different antibodies, and few of them have been replicated across cohorts and assay platforms to undergo further standardization and application
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