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.
Neurology. 2020 Oct 20;95(16):e2295-e2304. doi: 10.1212/WNL.0000000000010643. Epub 2020 Sep 2.
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.
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 ε4 genotype and CSF biomarker evidence of AD pathology were also assessed.
aCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, = 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, < 0.001) for incident MCI relative to aCH-/ε4-), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, < 0.001) increased risk relative to aCH-/CSF-. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory ( = -2.35, = 0.02) and language ( = -2.35, = 0.02), with effects exacerbated in individuals with AD risk factors.
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.
确定认知正常的老年人群中抗胆碱能药物（aCH）的认知后果，以及遗传和 CSF 阿尔茨海默病（AD）风险因素的相互作用。
共评估了来自阿尔茨海默病神经影像学倡议的 688 名认知正常的参与者（平均年龄 73.5 岁，49.6%为女性）。Cox 回归分析考察了在 10 年内进展为轻度认知障碍（MCI）的风险，线性混合效应模型则考察了 aCH 对记忆、执行功能和语言的 3 年下降率的影响。还评估了与 ε4 基因型和 CSF 生物标志物 AD 病理的相互作用。
aCH+参与者进展为 MCI 的风险增加（风险比 [HR] 1.47， = 0.02），并且存在 aCH × AD 风险的显著相互作用，使得 aCH+/ε4+个体发生 MCI 的风险增加了 2 倍以上（HR 2.69， < 0.001），而 aCH+/CSF+个体的风险增加了 4 倍以上（HR 4.89， < 0.001）。线性混合效应模型显示，aCH 预测记忆（ = -2.35， = 0.02）和语言（ = -2.35， = 0.02）的下降斜率更陡峭，而在具有 AD 风险因素的个体中，这种影响更为明显。
aCH 增加了发生 MCI 和认知下降的风险，并且在具有遗传风险因素和 CSF 基于 AD 病理生理标志物的个体中，影响明显增强。研究结果强调了 aCH 药物对认知的不良影响，以及需要进行药物去适应试验，尤其是在 AD 风险较高的人群中。
