Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults

ObjectiveTo determine the cognitive consequences of anticholinergic medications (aCH) in cognitively normal older adults as well as interactive effects of genetic and CSF Alzheimer disease (AD) risk factors. MethodsA total of 688 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative were evaluated (mean age 73.5 years, 49.6% female). Cox regression examined risk of progression to mild cognitive impairment (MCI) over a 10-year period and linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of aCH. Interactions with APOE ε4 genotype and CSF biomarker evidence of AD pathology were also assessed. ResultsaCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, p = 0.02), and there was a significant aCH × AD risk interaction such that aCH+/ε4+ individuals showed greater than 2-fold increased risk (HR 2.69, p < 0.001) for incident MCI relative to aCH−/ε4−), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, p < 0.001) increased risk relative to aCH−/CSF−. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory (t = −2.35, p = 0.02) and language (t = −2.35, p = 0.02), with effects exacerbated in individuals with AD risk factors. ConclusionsaCH increased risk of incident MCI and cognitive decline, and effects were significantly enhanced among individuals with genetic risk factors and CSF-based AD pathophysiologic markers. Findings underscore the adverse impact of aCH medications on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD.