Is Alzheimer's Risk Lower With TNF Inhibitors? Save

Tumor necrosis factor (TNF) inhibitors for rheumatoid arthritis were linked with a lower risk of Alzheimer's disease and related dementia, but only in people with cardiovascular disease, data from the DREAM (Drug Repurposing for Effective Alzheimer's Medicines) study showed.

Among more than 22,000 older adults, targeted disease-modifying antirheumatic drugs overall were not associated with a reduced risk of Alzheimer's disease and dementia, reported Rishi Desai, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and co-authors.

However, a subgroup of people with cardiovascular disease whose arthritis was treated with TNF inhibitors showed a potentially lower risk of Alzheimer's and dementia, the researchers reported in JAMA Network Open.

Other research has suggested that anti-TNF drugs may reduce Alzheimer's risk. "TNF-alpha is a key mediator of inflammation," co-author Madhav Thambisetty, MD, PhD, of the NIH National Institute on Aging, told MedPage Today. "The links between higher levels of inflammation and both cardiovascular disease and Alzheimer's disease are well known."

"Our findings from the DREAM study suggest that in some rheumatoid arthritis patients with co-existing heart disease, TNF-alpha inhibitors may lower the risk of incident Alzheimer's disease," Thambisetty said. "These results are especially significant given a recent large genome-wide association study suggesting that genetic variants related to TNF-alpha signaling may be causally linked to Alzheimer's."

"The molecular mechanisms underlying these findings remain to be identified, although accumulating evidence suggests that targeting systemic or peripheral inflammation in subgroups of patients who might benefit the most may be a promising approach to disease modification," he added.

In the DREAM study, cytokine signaling, including TNF and interleukin (IL)-6 through the Janus kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to modify the risk of Alzheimer's disease and related dementia.

Desai and co-authors evaluated 22,569 propensity score-matched pairs among Medicare fee-for-service rheumatoid arthritis patients ages 65 and older from 2007 to 2017. The researchers grouped patients into three cohorts based on initiation of the JAK inhibitor tofacitinib (Xeljanz), the IL-6 inhibitor tocilizumab (Actemra), or TNF inhibitors, assessing them against a common comparator, the T-cell activation inhibitor abatacept (Orencia).

The main outcome was onset of Alzheimer's and related dementia based on diagnosis codes. The researchers evaluated 4,224 tofacitinib pairs (mean age 72, 82% women), 6,369 tocilizumab pairs (mean age 72, 79% women), and 11,976 TNF inhibitor pairs (mean age 73, 82% women). Diabetes and hypertension were common in all three cohorts.

There were no statistically significant associations overall between incident Alzheimer's and dementia with tofacitinib, tocilizumab, or TNF inhibitors, compared with abatacept.

Subgroup analyses by age, sex, and baseline cardiovascular disease showed results consistent with the main analyses, except for patients with cardiovascular disease on TNF inhibitors. For these patients, point estimates indicated a lower incidence of Alzheimer's and dementia in two analyses: one incorporating a 6-month induction period (HR 0.74, 95% CI 0.56-0.99) and one that combined symptomatic prescriptions and diagnosis codes to identify Alzheimer's and dementia (HR 0.45, 95% CI 0.21-0.98).

"One key hypothesis that merits testing in future studies is that these patients may have significantly perturbed TNF-alpha signaling at baseline, and that correcting these abnormalities by TNF-alpha inhibitors mediates the protective effect on Alzheimer's disease," Thambisetty observed.

The study had several limitations, the researchers noted. Outcomes were small for tofacitinib and tocilizumab, partly owing to short mean follow-up duration. In addition, the pathogenesis of Alzheimer's and dementia may begin many years before a clinical diagnosis, and longer treatment or observation periods may be needed to draw firmer conclusions.

The findings about TNF inhibitors highlight why precision medicine may be important, Thambisetty pointed out. "A one-size-fits-all approach to treating and preventing Alzheimer's is unlikely to be as effective as identifying particular risk profiles of patients who may benefit from specific drugs to lower their risk of Alzheimer's disease," he said.

"In an ongoing study called PREVENT-AD, we are studying candidate Alzheimer's treatments such as TNF-alpha inhibitors to better understand their mechanisms of action relevant to Alzheimer's disease," he added. "These studies involve experimental validation in cell culture-based phenotypic screens, as well as experimental studies in relevant transgenic animal models of Alzheimer's."

Source Reference: Desai RJ, et al "Comparative risk of Alzheimer disease and related dementia among Medicare beneficiaries with rheumatoid arthritis treated with targeted disease-modifying antirheumatic agents" JAMA Netw Open 2022; DOI: 10.1001/jamanetworkopen.2022.6567.