Exploring the repurposing potential of β 2 -adrenergic receptor agonists for cognitive function: Evidence from the PharmLines Initiative Retrospective Cohort Study

Abstract

Background

Preclinical studies suggest β₂-adrenergic receptor agonists may exert neuroprotective effects, but evidence in human populations is limited.

Objective

To examine the association between β₂-adrenergic receptor agonist use and cognitive performance in older adults.

Methods

This retrospective cohort study linked Dutch pharmacy dispensing records (IADB.nl) with Lifelines cohort data. Participants aged ≥50 years with ≥1 prescription for β₂-adrenergic receptor agonists or reference medications (COPD/cardiovascular) within 365 days prior to baseline cognitive testing were included. Cognitive function was assessed using the Cogstate Brief Battery. Linear mixed models adjusted for demographic, clinical, and lifestyle factors evaluated longitudinal changes.

Results

A total of 3179 participants were included (249 β₂-adrenergic receptor agonist users, 2930 reference). The exposed group was younger (mean age 58.6 ± 7.4 years versus 63.7 ± 9 years) and included a higher proportion of females (68.2% versus 58.6%) compared with the referent group. At baseline, groups were similar in most cognitive domains, except for slightly higher attention (COG2) scores in the reference group (p = 0.010). Over time, psychomotor speed (COG1), attention (COG2), and visual learning (COG4) remained stable across groups. Working memory (COG3) declined significantly in both groups, with a steeper decline in the reference cohort (p = 0.048).

Conclusions

In this exploratory cohort study, β₂-adrenergic receptor agonist use was not associated with broad cognitive benefits, though a modest attenuation of working memory decline was observed. These results highlight the need for larger, prospective studies to clarify whether specific subgroups or drug formulations may offer cognitive advantages.