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

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-beta negative, cognitively unimpaired individuals (A beta- 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 A beta+ individuals with mild cognitive impairment (A beta+ MCI; n=150) or Alzheimer's disease dementia (A beta+ AD; n=139) to test whether the age predicted from proteins alone (inflammatory age) differed significantly from true chronological age. A beta- individuals with subjective cognitive decline (A beta- SCD; n=125) or MCI (A beta- 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 A beta- CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the A beta- SCD and validation A beta- CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in A beta- MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the A beta+ MCI and A beta+ AD groups, with varying degrees of change compared to A beta- CU and A beta- 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.

Automated summary

The study revealed that inflammatory proteins in both cerebrospinal fluid (CSF) and plasma are associated with cognitive impairment and AD pathology. The levels of inflammatory proteins varied across different stages of AD, with CSF inflammatory changes highly correlated with core AD biomarkers.