Parallel neuroinflammatory pathways to cerebrovascular injury and amyloid-beta in Alzheimer’s disease
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Importance
While the hallmark pathologies of amyloid-beta (Aβ) and tau in Alzheimer’s disease (AD) are well documented and even part of the definition, upstream neuroinflammation is thought to play an important role but remains poorly understood.
Objectives
We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular injury and Aβ, and whether these markers are associated with plasma phosphorylated tau (pTau) concentration, medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. We examined neuroinflammatory markers plasma YKL-40 and GFAP, due to previous conflicting evidence relating YKL-40 and GFAP to AD pathogenic markers.
Design
Cross-sectional data from a community observational study (Biomarker Exploration in Aging, Cognition, and Neurodegeneration - BEACoN) were included.
Setting
All participants were enrolled in a single site, at University of California, Irvine.
Participants
126 participants were included if they had at least one of the following measures available: neuropsychological data, MRI, Aβ-PET, or plasma.
Exposures
Plasma YKL-40 and plasma glial fibrillary acidic protein (GFAP) levels.
Main outcomes and measures
White matter hyperintensity (WMH) volume, 18F-florbetapir (FBP) PET mean SUVR, plasma phosphorylated tau (pTau-217) concentration, MTL cortical thickness, hippocampal volume, and memory function assessed by Rey Auditory Verbal Learning Test. Using path analysis, we tested whether higher plasma YKL-40 and GFAP are associated with WMH and Aβ, and whether these converge to downstream markers of tauopathy, MTL neurodegeneration, and memory deficits.
Results
In older adults without dementia (N=126, age=70.60 + 6.29, 62% women), we found that higher plasma YKL-40 concentration was associated with greater WMH volume, while higher plasma GFAP concentration was related to increased FBP SUVR. Further, higher plasma GFAP, WMH and FBP SUVR were independently associated with increased pTau-217. In turn, plasma pTau-217 was associated with reduced MTL cortical thickness and hippocampal volume. Subsequently, only reduced hippocampal volume was related to lower memory function.
Conclusions and Relevance
Neuroinflammatory markers contribute to parallel pathways of cerebrovascular injury and Aβ, which converge to tau-associated neurodegeneration and memory deficits in older adults. These observations underscore the need for a more comprehensive approach to developing an AD framework and treatment strategies.
KEY POINTS
Question
How does neuroinflammation impact downstream features of cerebrovascular injury and amyloid-beta (Aβ) in Alzheimer’s disease?
Findings
In this study of 126 older adults without dementia, we found evidence for two distinct neuroinflammatory pathways that lead to neurodegeneration and memory deficits. One path involves plasma YKL-40 and its impact on cerebrovascular injury, as measured by white matter hyperintensities (WMH) on MRI scans. The other involves plasma glial fibrillary acidic protein (GFAP) and its impact on Aβ deposition measured via 18F-florbetapir (FBP) PET. Both pathways converged on tauopathy, measured by plasma pTau-217, which was associated with lower medial temporal lobe (MTL) cortical thickness and hippocampal volume, and consequently, memory deficits.
Meaning
Inflammation acts on Alzheimer’s disease mechanisms via multiple distinct and parallel pathways which converge downstream onto neurodegeneration.
Graphical Abstract
Credit: BioRender was used to help create this graphical abstract.
