Accelerated inflammatory aging in Alzheimer's disease and its relation to amyloid, tau, and cognition

Abstract

It is unclear how pathological aging of the inflammatory system relates to Alzheimer's disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ- CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer's disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone ("inflammatory age") differed significantly from true chronological age. Aβ- individuals with subjective cognitive decline (Aβ- SCD; n = 125) or MCI (Aβ- MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ- CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ- SCD and validation Aβ- CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ- MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ- CU and Aβ- SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.

Figure 1

Predicting age from inflammatory proteins in Aβ-CU individuals. This figure shows the variance explained by linear regression models used to predict chronological age in amyloid-negative, cognitively unimpaired individuals from CSF and plasma proteins grouped into a range of inflammatory pathways.

Figure 2

CSF-based proteomic aging across inflammatory pathways. This figure shows the distribution of CSF-based inflammatory age scores (i.e. the age predicted for each individual from inflammatory proteins alone) across groups and inflammatory processes. The dotted line at zero indicates that the age predicted from an individual’s protein levels is the same as that individual’s chronological age—indicating an inflammatory age which is normal. Values above the dotted line indicate that an individual’s inflammatory proteome is more representative of a chronologically older individual.

Figure 3

Plasma-based proteomic aging across inflammatory pathways. This figure shows the distribution of plasma-based inflammatory age scores (i.e. the age predicted for each individual from inflammatory proteins alone) across groups and inflammatory processes. The dotted line at zero indicates that the age predicted from an individual’s protein levels is the same as that individual’s chronological age—indicating an inflammatory age which is normal. Values above the dotted line indicate that an individual’s inflammatory proteome is more representative of a chronologically older individual.

Figure 4

Association between CSF-based proteomic aging and core AD biomarkers. This figure shows the association between CSF-based InflammAGE scores (i.e. the difference between an individual’s inflammatory age and their chronological age) and various core biomarkers of AD—amyloid accumulation, tau accumulation, general neurodegeneration, and cognitive decline.

Figure 5

Association between Plasma-based proteomic aging and core AD biomarkers. This figure shows the association between plasma-based InflammAGE scores (i.e. the difference between an individual’s inflammatory age and their chronological age) and various core biomarkers of AD—amyloid accumulation, tau accumulation, general neurodegeneration, and cognitive decline.