Abstract:IntroductionThere is a significant need for disease-modifying therapies to treat and prevent dementia, including Alzheimer's disease. Availability of real-world observational information and new analytic techniques to analyze large volumes of data can provide a path to aid drug discovery.MethodsUsing a self-controlled study design, we examined the association between 2181 medications and incidence of dementia across four US insurance claims databases. Medications associated with ≥50% reduction in risk of demen… Show more
“… 37 , 38 However, a recent study examining medications associated with a decreased risk of dementia found no protective effects of TNFI therapies when using a self‐controlled cohort design, comparing use of TNFI versus no TNFI use. 39 …”
Introduction
Peripheral inhibition of tumor necrosis factor (TNF)‐α, outside of the central nervous system, may result in clinical improvement of Alzheimer's disease (AD) outcomes. TNF‐α inhibitors (TNFIs) are effective treatments for various autoimmune conditions and may be effective for preventing and/or treating AD. The objective of this study was to compare the risk of dementia and AD in patients initiating methotrexate versus those initiating TNFIs.
Methods
Insurance claims data from databases of commercially insured and Medicare‐eligible patients were used to estimate the risk of dementia and AD within patients with rheumatoid arthritis (RA) initiating a TNFI versus initiation of methotrexate. A sensitivity analysis included all patients without the RA diagnosis requirement. The at‐risk period spanned from the index date until a diagnosis of the outcome, loss‐to‐follow‐up, or receipt of the comparator drug. Patients were matched 1‐to‐1 using propensity scores. A Cox proportional hazards model was used to estimate the hazard ratio (HR). Negative controls were used to calibrate the results.
Results
A total of 11,092 new TNFI patients and 44,023 new methotrexate patients were identified, and 8925 from each group were matched. The outcome of dementia occurred in 1.4% of patients in both groups. The calibrated results from the Cox regression found no difference between the two groups (commercially insured database: calibrated HR = 0.69, 95% confidence interval = 0.45 to 1.05; Medicare‐only database: 1.14, 0.66 to 1.96). Results were similar in all sensitivity analyses: outcome of AD and including patients without RA.
Discussion
No significant difference for the risk of dementia or AD was seen between patients initiating a TNFI versus methotrexate. Although this study cannot conclude whether use of TNFIs is protective against dementia and AD compared with receiving no treatment, there was no evidence that it is more protective than the active comparator methotrexate.
“… 37 , 38 However, a recent study examining medications associated with a decreased risk of dementia found no protective effects of TNFI therapies when using a self‐controlled cohort design, comparing use of TNFI versus no TNFI use. 39 …”
Introduction
Peripheral inhibition of tumor necrosis factor (TNF)‐α, outside of the central nervous system, may result in clinical improvement of Alzheimer's disease (AD) outcomes. TNF‐α inhibitors (TNFIs) are effective treatments for various autoimmune conditions and may be effective for preventing and/or treating AD. The objective of this study was to compare the risk of dementia and AD in patients initiating methotrexate versus those initiating TNFIs.
Methods
Insurance claims data from databases of commercially insured and Medicare‐eligible patients were used to estimate the risk of dementia and AD within patients with rheumatoid arthritis (RA) initiating a TNFI versus initiation of methotrexate. A sensitivity analysis included all patients without the RA diagnosis requirement. The at‐risk period spanned from the index date until a diagnosis of the outcome, loss‐to‐follow‐up, or receipt of the comparator drug. Patients were matched 1‐to‐1 using propensity scores. A Cox proportional hazards model was used to estimate the hazard ratio (HR). Negative controls were used to calibrate the results.
Results
A total of 11,092 new TNFI patients and 44,023 new methotrexate patients were identified, and 8925 from each group were matched. The outcome of dementia occurred in 1.4% of patients in both groups. The calibrated results from the Cox regression found no difference between the two groups (commercially insured database: calibrated HR = 0.69, 95% confidence interval = 0.45 to 1.05; Medicare‐only database: 1.14, 0.66 to 1.96). Results were similar in all sensitivity analyses: outcome of AD and including patients without RA.
Discussion
No significant difference for the risk of dementia or AD was seen between patients initiating a TNFI versus methotrexate. Although this study cannot conclude whether use of TNFIs is protective against dementia and AD compared with receiving no treatment, there was no evidence that it is more protective than the active comparator methotrexate.
“…Figure 1 illustrates the study design for a single condition outcome. The REWARD framework has been used in previous studies examining treatments associated with the prevention of parkinsonism and Alzheimer’s disease [ 14 , 15 ]. Fig.…”
Section: Methodsmentioning
confidence: 99%
“…We have built upon advances in statistical methodologies and computing power to create the real-world assessment and research of drug performance (REWARD) framework for studying the association between thousands of medications with thousands of outcomes in millions of patients. Prior work leveraging this framework has focused on specific outcomes of interest to identify heretofore unappreciated uses of existing drugs to treat or prevent a specific disease [ 14 , 15 ]. In this study, we have taken the reverse approach, by examining exposure to a single drug, memantine, and measuring its association with all potential outcomes, in order to identify potential indications for new NMDA receptor antagonist therapies.…”
“…Parkinson's disease) (106,108). Dysregulated SGR in brain disorders like AD implicates a range of SGR-related processes involving molecular targets that could be therapeutically accessible by targeting variant genes, their expressed products or specific enzymes-for example, by using the RT inhibitors that are already approved by the Food and Drug Administration for treating HIV (106,109); post hoc literature analyses support potential benefits of RTs in AD (106,(109)(110)(111).…”
A new form of somatic gene recombination (SGR) has been identified in the human brain that affects the Alzheimer’s disease gene, amyloid precursor protein (APP). SGR occurs when a gene sequence is cut and recombined within a single cell’s genomic DNA, independent of DNA replication and the cell cycle. The newly identified brain SGR produces genomic complementary DNAs (gencDNAs) lacking introns, which integrate into locations distinct from germline loci. This brief review will present an overview of likely related recombination mechanisms and genomic cDNA-like sequences that implicate evolutionary origins for brain SGR. Similarities and differences exist between brain SGR and VDJ recombination in the immune system, the first identified SGR form that now has a well-defined enzymatic machinery. Both require gene transcription, but brain SGR uses an RNA intermediate and reverse transcriptase (RT) activity, which are characteristics shared with endogenous retrotransposons. The identified gencDNAs have similarities to other cDNA-like sequences existing throughout phylogeny, including intron-less genes and inactive germline processed pseudogenes, with likely overlapping biosynthetic processes. gencDNAs arise somatically in an individual to produce multiple copies; can be functional; appear most frequently within post-mitotic cells; have diverse sequences; change with age; and can change with disease state. Normally occurring SGR may represent a mechanism for gene optimization and long-term cellular memory, whereas its dysregulation could underlie multiple brain disorders and, potentially, other diseases like cancer. The involvement of RT activity implicates already FDA-approved RT inhibitors as possible near-term interventions for managing SGR-associated diseases and suggest next-generation therapeutics targeting SGR elements.
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