Abstract
Rheumatoid arthritis (RA) patients have been observed to be at a lower risk of developing Alzheimer’s Disease (AD). Clinical trials have showed no relationship between nonsteroidal anti-inflammatory drug (NSAID) use and AD. The aim of this study was to establish if there is a causal link between RA and AD. A systematic literature review on RA incidence and its link to AD was carried out according to the PRISMA guidelines. Eight case-control and two population-based studies were included in a random effects meta-analysis. The causal relationship between RA and AD was assessed using Mendelian Randomization (MR), using summary data from the largest RA and AD Genome Wide Association (GWA) and meta-analysis studies to date using a score of 62 RA risk SNPs (p < 5 * 10−8) as instrumental variable (IV). Meta-analysis of the literature showed that RA was associated with lower AD incidence (OR = 0.600, 95% CI 0.46–0.77, p = 1.03 * 10−4). On the contrary, MR analysis did not show any evidence of a causal association between RA and AD (OR = 1.012, 95% CI 0.98–1.04). Although there is epidemiological evidence for an association of RA with lower AD incidence, this association does not appear to be causal. Possible explanations for this discrepancy could include influence from confounding factors such as use of RA medication, selection bias and differential RA diagnosis.
Highlights
Information transfer at the synaptic junctions of the brain is compromised in Alzheimer’s Disease (AD) patients due to the accumulation of extracellular beta amyloid, which contributes to neuronal cell death
The overall results of the literature meta-analysis indicate that Rheumatoid arthritis (RA) was associated with lower AD risk (OR = 0.60, 95% CI 0.46–0.77; p = 1.03 * 10−4), the summary causal estimate from conventional Inverse-Variance Weighted (IVW) Mendelian Randomization (MR) showed no evidence to support a causal inverse association between RA and AD (OR = 1.018, 95% CI 0.98–1.06) (Table 2, Fig. 2)
The “leave one out” results show that by omitting the included 62 SNPs one at a time, no individual genetic variants seem to have any significant effect on the overall results and after excluding 20% of the SNPs at a time (100000 times) 0.009% of the sensitivity coefficients layed outside the MR 95% CI highlighting that these results are not sensitive to SNP selection
Summary
Information transfer at the synaptic junctions of the brain is compromised in AD patients due to the accumulation of extracellular beta amyloid, which contributes to neuronal cell death. Inside the neurons, increased levels of tau, a protein that stabilizes microtubules, forms neurofibrillary tangles that block transport of nutrition and necessary molecules throughout the cell. This process contributes to neuronal cell death[1]. Pharmacological treatments of AD are limited, with current therapies improving symptoms only transiently. (LPS) was used to produce chronic neuroinflammation in rats reproduced some of the features of AD, such as working memory deficit, elevated levels of beta amyloid precursor protein, and temporal lobe pathology associated with cell loss[5]. Neuroinflammation responses can be induced by both CNS-intrinsic factors and systemic influences[6] and a number of conditions such as diabetes[7], obesity[8], atherosclerosis[9], depression[10], psoriasis[11] and cardiovascular disease[12], which have been proposed as risk factors for the development of AD are associated with chronic inflammation[13]
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