Abstract
This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer's disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn's disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia
S2 Fig. Adjusted Odds Ratio (AOR) showing the inverse risk association between dementia and tumor necrosis factor (TNF) blocker or methotrexate compared to the no-drug group adjusting for age, gender, and race in patients with a diagnosis of rheumatoid arthritis who are non-smokers. (DOCX)
S3 Fig. Adjusted Odds Ratio (AOR) showing the inverse risk association between dementia and TNF blocker or methotrexate compared to the no-drug group adjusting for age, gender, and race in patients with a diagnosis of rheumatoid arthritis who are current non-drinker of alcohol. (DOCX)
Summary
Characteristic pathology in brain includes the presence of plaques (deposits of amyloid-β peptide) and tangles (intraneuronal deposits of hyperphosphorylated tau protein) [1, 2]. These occur in hippocampus and associational cortex, regions of the brain important for cognitive function. Accumulation of amyloid plaque occurs over many years and generally precedes accumulation of intraneuronal tangles and cognitive dysfunction [2]. Progression of disease is associated with neuronal degeneration, cortical thinning, and deepening and severe cognitive impairment. Elevation of TNF in cerebrospinal fluid collected from subjects with mild cognitive impairment is associated with progression to AD at 6 months follow up [6]. Multiple lines of evidence indicate that TNF may trigger or amplify aberrant microglia signaling in the brain [7,8,9,10] and thereby contribute to AD pathogenesis
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