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

Neurology. 2020 Oct 20;95(16):e2295-e2304. doi: 10.1212/WNL.0000000000010643. Epub 2020 Sep 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / epidemiology*
  • Alzheimer Disease / genetics
  • Apolipoproteins E / genetics
  • Biomarkers / cerebrospinal fluid
  • Cholinergic Antagonists / adverse effects*
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / epidemiology*
  • Cognitive Dysfunction / genetics
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Incidence
  • Male


  • ApoE protein, human
  • Apolipoproteins E
  • Biomarkers
  • Cholinergic Antagonists