Cumulative anticholinergic exposure and white matter hyperintensity burden in community-dwelling older adults

Background: Anticholinergic exposure is associated with dementia risk; however, the mechanisms for this association remain unclear. The objective of this study was to examine the association between anticholinergic exposure and white matter hyperintensity (WMH) burden.

Methods: This was a retrospective analysis of data from the Adult Changes in Thought (ACT) study, a prospective cohort study among adults aged ≥65 years on dementia risk factors. We used data collected through March 2020 for this analysis. The sample included ACT participants who were referred for and had a clinical magnetic resonance imaging (MRI) scan and ≥10 years of continuous healthcare enrollment prior to the scan. Our primary exposure was total standardized daily dose (TSDD) of anticholinergics. Outcomes included three semi-quantitative ratings of WMH volume. We used separate linear regression models for each outcome to estimate and compare covariate-adjusted mean values of WMH ratings in each exposure group.

Results: Of the 1043 individuals included in the analyses, 28% had no use, 33% had 1-90 TSDD, 15% had 91-365 TSDD, 7% had 366-1095 TSDD, and 17% had ≥1096 TSDD. The mean age was 81 years, most were female (58%) and White race (88%). Compared to those with no use, the ≥1096 TSDD group had a higher (worse) adjusted mean [95% confidence intervals] Fazekas (4.0 [3.8, 4.2] vs. 3.4 [3.2, 3.5]; p: <0.001), Modified Scheltens (14.3 [13.4, 15.2] vs. 12.2 [11.5, 12.9]; p: <0.001), and Age-Related White Matter Changes (5.6 [5.3, 6.0] vs. 4.8 [4.5, 5.1]; p = 0.001). A dose-response relationship was not found.

Conclusions: The highest anticholinergic exposure was associated with greater WMH burden. Future studies should focus on longitudinal changes of WMH burden to better understand the biological mechanisms underlying the link between anticholinergics and dementia risk.