Higher inflammation levels in cognitively normal older adults are associated with conversion to mild cognitive impairment and Alzheimer's disease. (1st February 2022)

• Record Type: Journal Article
• Authors: Contreras, Joey A; Aslanyan, Vahan; Albrecht, Daniel S; Pa, Judy
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-01
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.054590
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: There is growing evidence that Alzheimer's disease (AD) pathogenesis interacts with immunological mechanisms in the brain. CSF and blood inflammatory markers of the NF‐κß pathway, a key transcriptional regulator of inflammation involved in learning and memory, are elevated in cognitively normal older adults and those with early MCI. However, few studies have examined whether elevated inflammation predicts clinical conversion in cognitively normal older adults. Our study aimed to investigate the relationship between levels of TNF‐α, canonical trigger of NF‐κß pathway and IL‐9, a cytokine whose expression is driven by NF‐κß, and clinical conversion status. Method: 295 older adult participants (118 males, mean age+ SE=74.87+ 6.75, 124 APOE4 carriers) from ADNI were selected based on having available baseline CSF values and diagnoses for at least two timepoints. Cox proportional‐hazard models were used to test the association between baseline inflammatory markers and clinical conversion from cognitively normal to MCI or AD. Baseline age, sex, and APOE4 status were included as covariates. Additional analyses explored the modifying role of APOE4 on the relationship between CSF values and conversion. Result: Higher levels of TNF‐α were associated with greater conversion from cognitively normal (CN) to MCI (Hazard ratio (HR): 1.31, confidence interval (CI): 1.07, 1.59, p<0.01), and from CN and MCI to AD (HR: 1.13, CI: 1.01, 1.21, p =0.02), suggesting those who were cognitively normal with elevated TNF‐α levels had a 31% increased risk of conversion to MCI relative to those with lower TNF‐α levels. Higher IL‐9 was associated with a 37% increased risk of conversion to MCI (HR: 1.37, CI: 1.02, 1.84, p=0.04). Additionally, an APOE4‐to‐IL‐9 interaction was observed (HR: 2.46, CI: (1.34, 4.52), p<0.01), such that APOE4 carriers with higher IL‐9 levels were at greater risk for conversion than APOE4 non‐carriers (Fig 1). Conclusion: In cognitively normal older adults, higher levels of inflammatory markers TNF‐α and IL‐9 are associated with greater conversion to MCI and AD. This relationship is exacerbated in APOE4 carriers. Together, this suggests that early elevated inflammation levels are associated with subsequent cognitive decline and dementia risk and may be an earlier indicator of future conversion to MCI or AD.