Leukotriene receptor antagonist use is associated with slower cognitive decline in Alzheimer’s disease

Abstract Background Repurposing of leukotriene receptor antagonists (LTRAs), originally developed for asthma, is currently being explored in the treatment Alzheimer’s disease (AD). Animal studies have shown that administration of the LTRA montelukast has neuroprotective effects and can improve memory and cognition in rodents; however, there is limited evidence supporting the neuroprotective effects of LTRAs in humans. Methods Participants with AD dementia were identified in the National Alzheimer's Coordinating Center database. LTRA (montelukast or zafirlukast) users were propensity matched 1:3 to non‐users on age, sex, education, body mass index, smoking history, concomitant use of medications for dementia and other respiratory medications (for allergy, chronic obstructive pulmonary disease, and asthma), APOE ε4 carrier status, CDR® Dementia Staging Instrument global score, and vascular brain disease. Cognitive domains including immediate and delayed memory (Weschler Memory Scale Revised – Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol), and language (Animals, Vegetables, and Boston Naming Test) were compared between users and non‐users in mixed‐effects linear or Poisson regression models, as appropriate for the data distribution, yielding unstandardized regression coefficients (B) and rate ratios (RR), respectively. Results Among n=604 people with AD dementia (mean age 75.3±10.0 years, 59.3% female, mean education 14.0±4.0 years, 55.1% APOE ε4 carriers, mean follow‐up 2.5±2.6 years), LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol test (Β=1.466 [0.253,2.687] symbols/year), and a slower decline in language, as measured by Animals (Β=0.541 [0.215,0.866]animals/year), Vegetables (B=0.309 [0.056,0.561] vegetables/year), and the Boston Naming Test (B=0.529 [0.005,1.053] words/year). Effect sizes were relatively small (range 0.069‐0.101) and persisted after controlling for a 10% false discovery rate. LTRA use was not associated with a change in performance for immediate (RR=1.047 [0.970,1.129]) or delayed memory (RR=1.062 [0.929,1.215]). Conclusion These results indicate that use of an LTRA may have benefits for preserving function for select cognitive domains in individuals with AD dementia. The leukotriene pathway may represent a target for the treatment of AD dementia and the role of leukotrienes and their receptors in cognitive decline warrants further investigation.

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