Association between inflammatory biomarkers and cognitive aging

Abstract

Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer’s Disease, dementia, and cognitive disorders. We examined the association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.

Association between gut permeability, brain volume, and cognition in healthy participants and patients with schizophrenia spectrum disorder

“…sCD14 is negatively related to brain volumes in people with irritable bowel syndrome (IBS) (Weaver et al., 2016), supporting the idea that increased bacterial translocation negatively affects brain volume. Similarly, recent studies in elderly found that high levels sCD14 and other inflammatory markers are correlated to low brain volume, impaired cognition and incident dementia (Fang et al., 2022; Pase et al., 2020).…”

Peripheral inflammatory biomarkers are associated with cognitive function and dementia: Framingham Heart Study Offspring cohort

“…Our primary analyses focused on the three cognitive domain factor (2) CVD risk factors including systolic and diastolic blood pressures (mmHg), diabetes status, treatment for hypertension, body mass index (kg/m 2 ), current smoking status, total cholesterol level (mg/ dL), high-density lipoprotein cholesterol levels (HDL, measured in mg/dL), and use of lipid-lowering agents at Exam 7 Fang, Doyle, Chen, et al, 2022). Diabetes status was defined by whether any of the following was satisfied: use of antidiabetic medications, fasting blood glucose level ≥126 mg/dL, or random blood glucose level ≥198 mg/dL.…”

“…and myeloperoxidase (MPO) were associated with poor performance in NP tests regarding executive function (Fang, Doyle, Chen, et al, 2022). It only assessed APOE ε4 carrier status and individual NP tests rather than the cognitive factor scores in the three APOE strata.…”

RAGE Inhibitors in Neurodegenerative Diseases

“…Other polyphenolic compounds, including ss-caryophyllene and carnosic acid, and camellia oil were also demonstrated to show anti-inflammatory activity and thus act as potential neuroprotective compounds [ 85 , 88 , 89 ]. The RAGE-induced activation of CD5L, an inflammatory protein, leads to the decreased brain volumes, while higher circulating soluble RAGE (s-RAGE), which functions as a decoy receptor for RAGE, was associated with increased brain volumes in AD models [ 90 ]. High mobility group box1 (HMGB1), a nuclear protein, interacts with RAGE, thereby inducing various inflammatory pathways that would lead to neurological diseases, including AD, and cardiovascular diseases [ 20 ].…”