Parallel neuroinflammatory pathways to cerebrovascular injury and amyloid-beta in Alzheimer’s disease
Authors: Rizvi Batool , Adams Jenna N. , Bamford Alison , Kim Soyun , Sathishkumar Mithra , Tustison Nicholas J. , Taylor Lisa , Tuteja Nandita , McMillan Liv , Nan Bin , Cai Hengrui , Escalante Yuritza Y. , Meza Novelle , Harris Alyssa L. , Malhas Rond , Brickman Adam M. , Mapstone Mark , Thomas Elizabeth A. , Yassa Michael A. 
Published: October 2024

ABSTRACTImportanceWhile 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.ObjectivesWe 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.DesignCross-sectional data from a community observational study (Biomarker Exploration in Aging, Cognition, and Neurodegeneration - BEACoN) were included.SettingAll participants were enrolled in a single site, at University of California, Irvine.Participants126 participants were included if they had at least one of the following measures available: neuropsychological data, MRI, Aβ-PET, or plasma.ExposuresPlasma YKL-40 and plasma glial fibrillary acidic protein (GFAP) levels.Main outcomes and measuresWhite 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.ResultsIn 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 RelevanceNeuroinflammatory 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 POINTSQuestionHow does neuroinflammation impact downstream features of cerebrovascular injury and amyloid-beta (Aβ) in Alzheimer’s disease?FindingsIn 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.MeaningInflammation acts on Alzheimer’s disease mechanisms via multiple distinct and parallel pathways which converge downstream onto neurodegeneration.Graphical AbstractCredit:BioRender was used to help create this graphical abstract.