Anticholinergic drugs and forebrain MRI changes in cognitively normal and mildly impaired people

Abstract Background Anticholinergic (AC) medication use is associated with cognitive decline and dementia, which may be related to an AC induced central hypocholinergic state, but the exact mechanisms remain to be understood. We aimed to further elucidate the putative link between AC drug prescription, cognition and structural and functional impairment of the forebrain cholinergic nucleus basalis of Meynert (NBM). Methods Cognitively normal (CN, n = 344) and mild cognitively impaired (MCI, n = 224) ADNI-3 participants who had undergone 3T-MRI were included. Structural (regional grey matter [GM] density) and functional NBM integrity (functional connectivity [FC]) were compared between those on anticholinergic medication for over one year (AC+) and those without (AC−) in each condition. AC burden was classes as mild, moderate or severe. Results 31% of participants were AC+ (≥ 1 mild AC drug) demonstrating lower NBM-GM density in CN (CNAC−: 0.6 ± 0.03; CNAC+: 0.6 ± 0.02; P < 0.001), and MCI subgroups (MCIAC−: 0.6 ± 0.03; MCIAC+: 0.6 ± 0.03; P < 0.001), but with a larger effect size in MCI. NBM-FC was lower in CNAC+ vs. CNAC− (3.6 ± 0.5 vs. 3.9 ± 0.6; P = 0.001), and in MCI (MCIAC+ 3.3 ± 0.2 vs. vs. MCIAC− 3.7 ± 0.5; P < 0.001) again with larger effect size in MCI. NBM-FC partially mediated the association between AC medication burden and cognition. Conclusions Our findings provide novel support for a detrimental effect of mild AC medication on the forebrain cholinergic system characterised as functional central hypocholinergic that partially mediated AC-related cognitive impairment. Moreover, structural tissue damage suggests neurodegeneration, and larger effect sizes in MCI point to enhanced susceptibility for AC medication in those at risk of dementia.