Which Aspects of Inflammation are Important in Alzheimer's Disease?
Researchers are coming to see chronic inflammation as an important driving mechanism of Alzheimer's disease, as well as many other age-related conditions. But inflammation is by no means a single, simple state. The immune system is complex, and inflammation is a complex collection of contributions and behaviors undertaken by varied cell populations. Researchers here find a way to gain some insight into which aspects of the inflammatory state are more or less important in the progression of Alzheimer's disease.
Inflammation is a central component of Alzheimer's disease (AD) pathophysiology, downstream of amyloid beta (Aβ) and tau pathology. Results become heterogeneous when one concentrates on single inflammatory markers, however. These variations may reflect different inflammatory mechanisms in different disease stages. However, a more parsimonious interpretation should take into account that cerebrospinal fluid (CSF) markers are only surrogate measures for an underlying construct, that is, inflammation, which cannot be directly observed in clinical studies.
Mathematically, one can express this epistemological reservation in the framework of structural equation models (SEM). We can construct the inflammatory response in the brain as a latent factor that eludes direct observation but can be assessed by observable proxy markers in the CSF. Confirmatory factor analysis is a readily available tool to form such latent factors. Here, we constructed latent factors for a priori defined inflammatory domains, including synaptic integrity, microglia, complement factors, adhesion, and cytokines/chemokines. We had two goals: First, to determine latent factors of neuroinflammation based on an a priori assignment of single inflammatory markers to certain inflammatory domains. Second, to characterize these neuroinflammation factors in relation to AD pathology markers from CSF and longitudinal rates of cognitive decline.
We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in CSF. We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.