Higher baseline levels of CSF inflammation increase risk of incident mild cognitive impairment and Alzheimer's disease dementia

Abstract

Introduction Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E ( APOE ) ε4 were also examined. Results Elevated levels of tumor necrosis factor α (TNF‐α), interleukin (IL)‐9, and IL‐12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF‐α and all APOE ε4 carriers with elevated IL‐9 levels had shorter times to conversion. In addition, TNF‐α mediated the relationship between elevated IL‐12p40 and IL‐9. Discussion Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.

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“…C-reactive protein, an indicator of systemic inflammation, was significantly lower in those who regularly took glucosamine, according to data from the National Health and Nutrition Examination Survey (NHANES) [8]. Animal studies also showed that glucosamine might suppress neuroinflammation [75], which is proved to increase the risk of dementia [76]. Furthermore, a prior research discovered that glucosamine might simulate a low-carbohydrate diet in mice through lowering glycolysis and enhancing amino acid catabolism [77]: consequently, glucosamine has been considered a mimicking agent for energy restriction [21].…”

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“…Some evidence suggests that air pollution has a greater negative impact on cognition in females (Kim et al, 2019). In a rat model of AD, exposure to traffic-related air pollution induced earlier and more profound amyloid pathology in females compared with males (Patten et al, 2021) Inflammation Data from a longitudinal study with >38,000 individuals found that APOE-ε4 carriers and females with higher CSF TNF-α, IL-9, and IL-12p40 levels were at the highest risk of progression to MCI/AD (Contreras et al, 2022).…”

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“…Other markers of neuroinflammation have been associated with AD pathogenesis in recent studies. CSF IL‐12p40, TNF‐α, and IL‐9, biomarkers involved in the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) pathway that transcriptionally regulates many genes involved in immune response, were associated with clinical progression to MCI or AD 183 . CSF progranulin acted in a protective manner.…”

“…The detrimental effects of neuroinflammation appear to be exacerbated by various other factors such as sex, APOE status, and cerebrovascular disease. Female APOE ε4 allele carriers with high levels of CSF IL‐12p40, TNF‐α, and IL‐9 had the greatest risk of progression, 183 and higher levels of CSF sTNFR2 were associated with worse cognition, mediated by CSF p‐tau181, in women but not men 185 . Higher levels of eight proinflammatory CSF biomarkers combined with lower levels of cerebrovascular disease, measured by pulse pressure, were associated with higher levels of CSF Aβ42 in CU ADNI participants 186 .…”