Alexandra J Weigand1, Mark W Bondi1, Kelsey R Thomas1, Noll L Campbell1, Douglas R Galasko1, David P Salmon1, Daniel Sewell1, James B Brewer1, Howard H Feldman1, Lisa Delano-Wood2. 1. From the San Diego Joint Doctoral Program in Clinical Psychology (A.J.W.), San Diego State University/University of California; Veterans Affairs San Diego Healthcare System (M.W.B., D.R.G., L.D.-W.); Department of Psychiatry (M.W.B., K.R.T., D.R.G., D.S., L.D.-W.), Alzheimer's Disease Research Center (M.W.B., D.R.G., D.P.S., D.S., J.B.B., H.H.F., L.D.-W.), and Department of Neurosciences (D.R.G., D.P.S., J.B.B., H.H.F.), University of California, San Diego; Center for Aging Research (N.L.C.), Regenstrief Institute, Inc. and Indiana University, Indianapolis; and Department of Pharmacy Practice (N.L.C.), Purdue University, West Lafayette, IN. 2. From the San Diego Joint Doctoral Program in Clinical Psychology (A.J.W.), San Diego State University/University of California; Veterans Affairs San Diego Healthcare System (M.W.B., D.R.G., L.D.-W.); Department of Psychiatry (M.W.B., K.R.T., D.R.G., D.S., L.D.-W.), Alzheimer's Disease Research Center (M.W.B., D.R.G., D.P.S., D.S., J.B.B., H.H.F., L.D.-W.), and Department of Neurosciences (D.R.G., D.P.S., J.B.B., H.H.F.), University of California, San Diego; Center for Aging Research (N.L.C.), Regenstrief Institute, Inc. and Indiana University, Indianapolis; and Department of Pharmacy Practice (N.L.C.), Purdue University, West Lafayette, IN. ldelano@ucsd.edu.
Abstract
OBJECTIVE: To 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. METHODS: A 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. RESULTS: aCH+ 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. CONCLUSIONS: aCH 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.
OBJECTIVE: To 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. METHODS: A 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. RESULTS: aCH+ 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. CONCLUSIONS: aCH 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.
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