Chronic low-grade inflammation (or “inflammaging”) is a common hallmark of ageing and is associated with diabetes, obesity and cardiovascular disease (Franceschi et al., 2018, Franceschi et al., 2017, Franceschi et al., 2001). Inflammaging, detected as elevated concentrations of circulating pro-inflammatory cytokines, has been previously associated with the development of both Mild Cognitive Impairment [MCI] and dementia (Brosseron et al., 2014, Engelhart et al., 2004, Ng et al., 2018, Pagoni et al., 2022, Roberts et al., 2009, Tan et al., 2007). Additionally, many of the risk factors for cognitive decline and dementia such as midlife obesity and diabetes are also associated with a pro-inflammatory state (Donath and Shoelson, 2011, Dyer et al., 2020, Livingston et al., 2020). Understanding the subtle relationships between peripheral inflammatory markers and domain-specific cognitive function in those without established cognitive impairment or dementia may aid in understanding the early stages in the complex relationship between inflammaging and cognitive decline in older adults. Importantly, this understanding may help in selecting-out individuals for potential interventions that may reduce the risk of cognitive decline and dementia.

Several studies have examined the relationship between circulating inflammatory markers and cognitive function in older adults. However, results are mixed and vary by cytokine studied - most commonly Interleukin-6 [IL-6] and C-Reactive Protein [CRP], assay used, cognitive tests used, and study sample size/design resulting in considerable heterogeneity within the published literature (Fard et al., 2022). Several cross-sectional and longitudinal studies have demonstrated associations between greater concentrations of IL-6 and/or CRP and poorer performance on the Mini-Mental State Examination (MMSE) and other brief tests of global cognitive function (Economos et al., 2013, Weaver et al., 2002, Yaffe et al., 2003, Zheng and Xie, 2018), although negative studies also exist (Dik et al., 2005). Despite this heterogeneity, there is mounting evidence for an association between elevated inflammatory markers and global cognitive decline in older adults without established dementia.

More detailed studies examining the relationship between inflammatory markers and domain-specific cognitive function have demonstrated associations primarily with executive function, processing speed and visuospatial ability (Fard et al., 2022). In the Berlin Aging Study of over one-thousand individuals, greater IL-6 and CRP concentrations were associated with poorer performance on tests of executive function (Tegeler et al., 2016), a finding which was previously seen in the Rotterdam Study (Schram et al., 2007). In the Women’s Health and Ageing Study, mild or moderate elevations in IL-6 were associated with declines in psychomotor speed over 9-years, but not in changes in executive function or memory (Palta et al., 2015). Meanwhile, in the Sydney Memory and Ageing Study of just-under nine-hundred participants, IL-6 concentrations were associated with poorer executive function and processing speed (Trollor et al., 2012) while cross-sectional associations between higher IL-6 and poorer visuospatial ability have also been reported elsewhere (Alley et al., 2008).

By contrast, a more-recent comprehensive study of over 1600 older adults from the Mayo Clinic Study of Aging did not demonstrate any cross-sectional or longitudinal associations between the inflammatory cytokines IL-6, Tumor Necrosis Factor-alpha [TNF-α], Interleukin-10 [IL-10] and domain-specific neuropsychological performance (Wennberg et al., 2019). This echoes previous negative findings from the Health, Ageing and Body Composition Study (Metti et al., 2014). In summary, these conflicting results mean the exact relationship between inflammatory markers and domain-specific cognitive performance in older adults without established dementia is currently not clear. Understanding this relationship may help identify those, with chronic inflammation at greatest risk of cognitive impairment and dementia, who may benefit from targeted and potentially preventative interventions (Hampel et al., 2020, Ngandu et al., 2015).

In order to add further clarity to the heterogenous and discrepant results from the literature to date, the cross-sectional and longitudinal relationships between serum concentrations of three inflammatory cytokines (IL-6, IL-10 and TNF-α) and detailed global and domain-specific cognitive performance were assessed in a large cohort of community-dwelling older adults, free from a diagnosis of dementia. It was hypothesised that higher concentrations of pro-inflammatory cytokines (IL-6, TNF- α) and lower concentrations of anti-inflammatory cytokines (IL-10) are associated with poorer global and domain-specific cognitive performance in dementia-free older adults.