Cardiometabolic medication exposures and cognitive outcomes in Alzheimer’s disease
Abstract
Abstract Background People with dementia are often prescribed cardiometabolic medications; however, the impact of this medication exposome on cognitive trajectories remains unclear. Methods We analysed data from National Alzheimer’s Coordinating Center (n = 28 044), Australian Imaging, Biomarkers and Lifestyle study (n = 1708) and Health and Aging Brain Study: Health Disparities (n = 1425) to examine associations between seven classes of cardiometabolic medications and cognitive outcomes [CDR sum of boxes (CDR-SB)], using linear mixed-effects models with time-varying exposure. Subgroup analyses were conducted by sex, apolipoprotein E (APOE) ε4, baseline age group and four progression groups [i.e. non-progression, cognitively unimpaired-to-mild cognitive impairment (CU-to-MCI), CU/MCI-to-Alzheimer’s dementia (ADem) progression and ADem-stable group]. A meta-analysis was also performed. Results Angiotensin-converting enzyme inhibitors and metformin were associated with a slower cognitive decline. Diuretics showed comparable associations, although these effects were restricted to specific subgroups. Statins exhibited divergent, stage-specific associations, with inverse associations observed in the CU/MCI-to-ADem subgroup and positive associations in the ADem-stable subgroup. Angiotensin II receptor blockers were associated with a greater longitudinal increase in CDR-SB among participants in the non-progression subgroup. Calcium channel blockers showed limited subgroup-specific cognitive benefit but were also associated with an accelerated increase in CDR-SB over time. β-blockers demonstrated no consistent association with cognitive trajectories, with evidence of a lower CDR-SB slope observed only in a cohort-specific analysis. Discussion Future research should incorporate pharmacy-verified medication exposure, explicit dosing information and dynamically modelled trajectories, while routinely assessing baseline and follow-up cognitive outcomes in pharmacotherapy trials involving older adults.