Rheumatoid arthritis (RA) and Alzheimer’s disease (AD) are both inflammatory diseases afflicting millions of individuals in the United States. RA affects up to 1.36 million US adults, according to conservative estimates, while AD is believed to affect more than 5.5 million Americans.1,2 As noted in a review published in April 2020 in Cureus, a small but growing body of research indicates the possibility of mechanistic links between RA and AD and other forms of dementia, as well protective or exacerbating effects of antirheumatic drugs on dementia risk.3

Systemic inflammatory disease is a significant risk factor for dementia, and it has been proposed that reductions in cerebral blood flow resulting from ongoing inflammation in RA may ultimately lead to dementia in some patients.3 Additionally, the systemic production of tumor necrosis factor (TNF) in RA and other inflammatory diseases involving TNF may directly contribute to neuroinflammation involved in the pathogenesis of AD.4

A population-based study (n = 1449) found associations between the presence of joint disorders in midlife and worse cognitive status at follow-up 21 years later.5 After adjustment for age, gender, smoking history, and other variables, the odds ratio (OR) for declining cognitive function was 1.96 (95% CI, 1.17-3.28) among participants with any joint disorder and 2.77 (95% CI, 1.26-6.10) for those with RA specifically. In addition, RA was significantly associated with Alzheimer’s disease (OR, 2.49; 95% CI, 1.09-5.67).

Subsequent studies have focused on links between antirheumatic drugs and the risk of dementia. A 2016 nested case-control study of more than 8.5 million adults in the United States with private insurance revealed a higher prevalence of AD among patients with RA compared to those without RA (0.79% vs 0.11%, P <.0001). However, RA patients who were taking etanercept demonstrated a lower risk of AD (adjusted OR [aOR], 0.30; 95 % CI, 0.08–0.89; P =.02).6


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A retrospective case-control study published in 2020 supports and expands upon those findings, further pointing to a potential protective role of anti-TNF agents against AD in RA patients.4 Analyses of data pertaining to 56 million US adults with commercial insurance, Medicare, or Medicaid revealed that while RA was linked to a higher AD risk (aOR, 2.06; 95% CI, 2.02–2.10; P <.0001), this risk was lower for patients receiving etanercept (aOR, 0.34; 95% CI, 0.25–0.47; P <.0001), adalimumab (aOR, 0.28; 95% CI, 0.19–0.39; P <.0001), or infliximab (aOR, 0.52; 95% CI, 0.39–0.69; P <.0001). There was also a lower risk for AD in psoriasis patients taking etanercept (aOR, 0.47; 95% CI, 0.30–0.73) and adalimumab (aOR, 0.41; 95% CI, 0.20–0.76).

“Biologic drugs such as etanercept and adalimumab distribute poorly to brain, so we presume the TNF blockers act systemically to prevent TNF from reaching the brain and thereby prevent or delay the onset of AD,” the authors explained.4 “Our study indicates that systemic inflammatory conditions involving TNF are a potentially treatable risk factor for AD,” and that treating RA with TNF inhibitors might help to prevent roughly 4.0% of AD cases (0.21 million).

The researchers also observed a lower risk for AD among RA patients taking methotrexate, which aligns with results of a retrospective matched case-control study of RA patients older than 50 years (486 with dementia and 641 controls) across 4 countries.7 In findings published in 2020 in Alzheimer’s Research and Therapy, patients with a history of methotrexate use demonstrated a lower risk of dementia (OR, 0.71, 95% CI, 0.52–0.98), with the lowest risk associated with methotrexate use longer than 4 years (OR, 0.37; 95% CI, 0.17–0.79).

Previous study results similarly found a reduced risk of dementia among RA patients taking methotrexate (hazard ratio, 0.52; 95% CI, 0.34–0.82) and other conventional disease-modifying antirheumatic drugs (cDMARDs).8

However, other research has produced conflicting results, including a 2017 study demonstrating an increased risk of dementia in RA patients with vs without cDMARD use (OR, 1.63; 95% CI, 1.33-2.00).9 A 2016 study reported an inverse association between prior RA and AD (aOR, 0.73; 95% CI, 0.55-0.98), and a 2017 meta-analysis also found that RA was associated with lower incidence of AD (OR, 0.600; 95% CI, 0.46–0.77; P =1.03 * 10−4).10,11

Further research is needed to elucidate the RA-dementia connection and the effects of various antirheumatic drugs on the risk of dementia in this patient population.

We checked in with Linda A. Russell, MD, rheumatologist and director of perioperative medicine at Hospital for Special Surgery in New York, to learn more about the clinical implications of the research findings in this area to date.

What does the available evidence suggest thus far about the possible mechanisms driving the connection between RA and dementia?

Most but not all studies suggest that there is an increased risk of dementia in patients with RA. RA is associated with systemic inflammation, which has already been shown to be associated with increased cardiovascular disease. This has been well studied in RA and lupus. It has been shown that RA can increase the risk of myocardial infarction and stroke.7 It is felt that the systemic inflammation in RA can be associated with the microvascular disease in vascular dementia.3

In addition, many patients with RA take glucocorticoids, and these can be associated with weight gain and elevated lipid levels, both of which can increase the risk of cardiovascular disease. Patients with RA may be relatively inactive compared to patients without RA, and this can also increase the risk of cardiovascular disease.

What are the relevant implications for clinicians regarding risk management and treatment selection in RA patients?

Several studies have shown that patients on anti-TNF therapy maybe somewhat protected from developing dementia. Anti-TNF therapy has been shown to decrease the risk of cardiovascular disease and bone loss in patients with RA; in both instances, the anti-TNF therapy is felt to decrease inflammation.12,13 Some studies have shown a similar effect with DMARDs, while other studies have not.

It is also important to control hypertension, hyperlipidemia, and diabetes, all of which can increase the risk of dementia. Patients should get regular exercise and maintain a healthy weight. One study demonstrated that patients with RA who participated in a regular rehabilitation program had less dementia than those patients who did not.14

What are remaining research needs pertaining to this topic?

In general, there has not been a big focus on dementia in RA. Given that we know there is an increased risk of cardiovascular disease in RA, it seems prudent to better explore ways to decrease the risk of dementia in patients with RA. There are many biologics in which this has not been evaluated. Additionally, the detrimental risk of glucocorticoids should be better explored.

References

  1.  Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol Int. 2017;37(9):1551-1557. doi:10.1007/s00296-017-3726-1
  2. NIH National Institute on Aging. Alzheimer’s disease fact sheet. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet. Accessed online October 5, 2020.
  3. Sangha PS, Thakur M, Akhtar Z, Ramani S, Gyamfi RS. The link between rheumatoid arthritis and dementia: a review. Cureus. 2020;12(4):e7855. doi:10.7759/cureus.7855
  4. Zhou M, Xu R, Kaelber DC, Gurney ME. Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS One. 2020;15(3):e0229819. doi:10.1371/journal.pone.0229819
  5. Wallin K, Solomon A, Kåreholt I, Tuomilehto J, Soininen H, Kivipelto M. Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population-based study. J Alzheimers Dis. 2012;31(3):669-676. doi:10.3233/JAD-2012-111736
  6. Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for rheumatoid arthritis and risk of Alzheimer’s disease: a nested case-control analysis. CNS Drugs. 2016;30(11):1111-1120. doi:10.1007/s40263-016-0374-z
  7. Newby D, Prieto-Alhambra D, Duarte-Salles T, et al. Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study. Alzheimers Res Ther. 2020;12(1):38. doi:10.1186/s13195-020-00606-5
  8. Judge A, Garriga C, Arden NK, et al. Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients. Alzheimers Dement (N Y). 2017;3(4):612-621. doi:10.1016/j.trci.2017.10.002
  9. Chou MH, Wang JY, Lin CL, Chung WS. DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: A propensity score-matched case-control study. Toxicol Appl Pharmacol. 2017;334:217-222. doi:10.1016/j.taap.2017.09.014
  10. Kao LT, Kang JH, Lin HC, Huang CC, Lee HC, Chung SD. Rheumatoid arthritis was negatively associated with Alzheimer’s disease: a population-based case-control study. PLoS One. 2016;11(12):e0168106. doi:10.1371/journal.pone.0168106
  11. Policicchio S, Ahmad AN, Powell JF, Proitsi P. Rheumatoid arthritis and risk for Alzheimer’s disease: a systematic review and meta-analysis and a Mendelian Randomization study. Sci Rep. 2017;7(1):12861. doi:10.1038/s41598-017-13168-8
  12. Veldhuijzen van Zanten JJCS, Sandoo A, Metsios GS, Stavropoulos-Kalinoglou A, Ntoumanis N, Kitas GD. Comparison of the effects of exercise and anti-TNF treatment on cardiovascular health in rheumatoid arthritis: results from two controlled trials. Rheumatol Int. 2019;39(2):219-225. doi:10.1007/s00296-018-4183-1
  13. Al-Bogami M, Bystrom J, Clanchy F, et al. TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20. Rheumatology (Oxford). Published online September 27, 2020. doi:10.1093/rheumatology/keaa551
  14. Lu MC, Livneh H, Yen CT, et al. Association of use of rehabilitation services with development of dementia among patients with rheumatoid arthritis: analysis of domestic data in Taiwan. Front Med (Lausanne). 2020;7:446. doi:10.3389/fmed.2020.00446