Anticholinergic Medications Associated With Increased Risk of MCI and Cognitive Decline


Linear mixed effects models revealed that anticholinergic medications predicted a steeper slope of decline in memory and language with effects exacerbated in individuals with Alzheimer disease risk factors.

Alexandra Weigand, BA

Newly published data suggest that anticholinergic medications (aCH) increase the risk of incident mild cognitive impairment (MCI) and cognitive decline, with those effects significantly raised in individuals with genetic risk factors and cerebrospinal fluid (CSF)-based Alzheimer disease (AD) pathophysiological markers.

Among a cohort of 688 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age, 73.5 years; 49.6% female), those on aCH medicines (aCH+) had an increased risk of progression to MCI (hazard risk [HR], 1.47; P = .02). Among the 688 participants, 230 (33%) were aCH+, with 73 of them being high aCH+. High aCH+ was categorized by taking 1 or more medications with an Anticholinergic Cognitive Burden (ACB) Scale of 2 or 3.

Alexandra Weigand, BA, graduate student, University of California–San Diego, and colleagues found that there was a significant aCH to AD-risk interaction. Data showed that aCH+ individuals who had positive APOE ε4 genotype (ε4+) had greater than a 2-fold increased risk (HR, 2.69; P <.001) for incident MCI relative to aCH- and ε4-.

Weigand et al. concluded that the “findings of this study underscore the potential for negative consequences of aCH in older adults and support deprescribing trials, especially for individuals with elevated risk for AD."

READ MORE: Building on Advancements in Alzheimer Disease Diagnostic Methods

CSF AD pathology was assessed as the ratio of p-tau181 and amyloid-beta1-42 (p-tau/Aß). Those with aCH+ and p-tau/Aß+ demonstrated greater than 4-fold (HR, 4.89; P <.001) increased risk relative to aCH- and p-tau/Aß-.

Weigand and colleagues aimed to determine the cognitive consequences of aCH in cognitively normal older adults as well as interactive effects of genetic and CSF AD risk factors. They used Cox regression models to assess the risk of progression to MCI over a 10-year period, as well as linear mixed effects models to examine 3-year rates of decline in memory, executive function, and language as a function of aCH.

There was a 3-way interaction between aCH, APOE status, and visit (F = 15.89; P <.001), such that the aCH+/ε4+ group exhibited a steeper decline in memory relative to the aCH-/ε4- group (t = –6.53; P <.001). Additionally, participants in the aCH+/ε4+ group also exhibited a steeper decline in memory relative to the aCH+/ε4- (t = –6.08; P <.001) and aCH-/ε4+ groups (t = 4.38; P <.001).

CSF risk interaction effects revealed an aCH by CSF interaction (log-likelihood ratio [LLR], 69.31; P < .001). As compared to the aCH-/ε4- group, aCH+/ε4+ participants had more than 2.5-fold risk of incident MCI (HR, 2.69; 95% CI, 1.78–4.07; P <.001).

When assessing the high aCH+ group relative to the aCH- group, the effect of aCH on risk of incident MCI was retained (HR, 2.11; 95% CI, 1.36–3.28; P <.001) such that high aCH+ participants demonstrated greater than 2-fold increased risk. Furthermore, compared to the aCH-/ε4- group, the high aCH+/ε4+ group had greater than 3-fold increased risk of incident MCI (HR, 3.35; 95% CI, 1.84–6.12; P <.001).

There was no 2-way interaction for the difference in baseline language score between aCH-/ε4- and aCH+/ε4+ groups (t = –.39; P = .69). However, there was a 3-way interaction between aCH, APOE status, and visit (F = 3.52; P = .02) such that the aCH+/ε4+ group exhibited a steeper decline in language relative to the aCH-/ε4- group (t = –3.22; P = .001).

Researchers documented no main effect of aCH (t = .52; P = .61) nor interaction between aCH and visit on executive function (t = –.59; P = .56), even when considering only high aCH+ participants (t = –.79; P = .43).

“Future studies investigating brain-based structural and functional changes associated with aCH and AD risk factors are warranted to further elucidate the mechanisms driving these consequences of aCH,” Weigand and colleagues concluded.

The role that the APOE ε4 allele plays in AD risk is well-documented. Katrina Celis, MD, postdoctoral fellow, University of Miami Miller School of Medicine, published a study earlier this year that suggested that the increased risk for AD seen in non-Hispanic Whites versus African American carriers of APOE ε4 is likely due to increased APOE ε4 expression in carriers with European genomic ancestry. Watch the conversation with Celis below.

Weigand A, Bondi MW, Thomas KR, et al. Association of anticholinergic medication and AD biomarkers with incidence of MCI among cognitively normal older adults. Neurology. Published online September 2, 2020. doi: 10.1212/WNL.0000000000010643
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