Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer’s dementia

Abstract

Background Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer’s disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time. Methods This longitudinal observational study used data from the National Alzheimer’s Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models. Results In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = −0.200 [−0.380, −0.019] points/year, n = 800) and AD dementia (B = −0.321 [−0.597, −0.046] points/year, n = 604) as measured by CDR Sum of Boxes. Conclusions The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.

Age-linked suppression of lipoxin A4 associates with cognitive deficits in mice and humans

“…Infiltration of immune cells, such as neutrophils [ 75 ], into the brain may shift cellular responses towards reduced LXA4 production and, consequently, increased neurotoxicity in AD. It is noteworthy that LXA4 is a potent antagonist of leukotriene receptors [ 76 ], and recent evidence supports that the use of leukotriene receptor antagonists brings cognitive benefits to AD-related dementia [ 77 ]. This suggests an indirect effect through which reduced central LXA4 contributes to worse cognition in AD.…”

Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review

“…The methodological quality of case–control studies included in this review was high in terms of participant selection, adjustment for covariates and exposure [ 10 , 16 , 20 , 25 ] compared to that of cohort studies. The representativeness of study cohorts was not adequate in eight cohort studies [ 7 – 9 , 11 , 12 , 24 , 27 , 30 ] because the associations were investigated only in specific subgroups of patients. Two studies scored low in quality assessment because no comparison cohort was present [ 18 ] and covariates were not adjusted in statistical analyses [ 24 ].…”

“…Montelukast may be associated with a reduced risk of developing pre-existing and new-onset dementia in observational studies. In a US study, montelukast was associated with a slower decline in cognitive test scores in patients with pre-existing Alzheimer's disease dementia [ 30 ]. Similar results were also identified in montelukast users in a Norwegian prescription study for the use of dementia medicine (adjusted HR 0.89, 95% CI 0.81–0.98) [ 12 ] and new-onset dementia (adjusted HR 0.42, 95% CI 0.20–0.87, p=0.019) in over 20 000 newly diagnosed asthma patients aged ≥50 years in Japan [ 8 ].…”

Computational Analysis of Pathogenetic Pathways in Alzheimer’s Disease and Prediction of Potential Therapeutic Drugs

“…Unexpectedly however, some of the drugs predicted to have a concordant signature with AD have previously been shown to be able to ameliorate the AD condition, as is the case for sorafenib [ 45 ] and montelukast [ 46 ]. Although this observation requires careful attention and validation in the in vivo setting, we may hypothesize that the pathways targeted by these drugs, rather than being pathological, may instead represent compensatory responses to the concomitant aberrant processes associated with the presence of fAD mutations.…”