Differential response to donepezil across MCI subtypes

A double-blind randomized controlled trial (RCT) finds that donepezil offers greater benefit in mild cognitive impairment (MCI) among individuals with hippocampal-sparing or minimal atrophy subtype vs individuals with typical or limbic-predominant patterns of atrophy.

Donepezil is an acetylcholinesterase inhibitor (AChE-I) widely used in symptomatic treatment of Alzheimer’s disease (AD) dementia. [Cochrane Database Syst Rev 2018;doi:10.1002/14651858.CD001190.pub3] However, evidence regarding donepezil’s efficacy in prodromal stages of AD has proved inconsistent so far. [Neurobiol Aging 2008;29:1285-1295] “The discrepancies may be explained by trial design insufficiencies and/or poor uniformity in eligibility criteria, with consequent inclusion of heterogeneous AD populations across trials, alongside lack of biomarker-based outcomes and endpoint assessments,” proposed the researchers.

The present RCT investigated response to donepezil in different MRI subtypes of individuals with amnestic MCI, which is considered the prodromal stage of AD dementia. The treatment group (n=83) received 5 mg of donepezil (one capsule) daily in weeks 0–6, followed by 10 mg of donepezil (two capsules) until month 12, which was matched in the placebo group (n=90). [Alzheimers Res Ther 2023;doi:10.1186/s13195-023-01253-2]

Participants were subtyped using the new continuous scale approach, but the researchers also reported results using the conventional categorical subtyping approach for comparison. Primary outcome was the rate of atrophy and secondary outcome was cognitive decline, both assessed over 1 year of donepezil treatment.

The researchers found significant interactions between treatment and hippocampus-to-cortex ratio in terms of AD signature cortical thickness (p=0.020) and volume of lateral ventricles (p=0.041), indicating that donepezil-treated individuals had less cortical thinning and ventricles expansion over time vs those who received placebo. This was particularly evident in individuals with more hippocampal-sparing–like MRI pattern. In contrast, changes in AD signature cortical thickness and lateral ventricles volume were comparable between donepezil and placebo groups among individuals with a more limbic-predominant–like MRI pattern.

A significant (p<0.001) interaction was also observed between treatment and brain volume–to–cerebrospinal fluid volume index, which is used as a proxy for the severity of global brain atrophy. Again, donepezil-treated individuals with more minimal atrophy-like MRI pattern had less cortical thinning over time vs those on placebo, while the changes in AD signature cortical thickness were comparable between the donepezil and placebo groups among individuals with a more typical-AD–like MRI pattern.

“The core result of this study was that individuals with MCI showed differential responses to donepezil treatment depending on their MRI patterns at baseline – a finding that emphasizes the role of biological heterogeneity when evaluating response to AChE-I treatments,” commented the researchers.

In contrast to the significant differences in response to donepezil treatment established when using continuous dimensions of heterogeneity, mixed analyses of variance showed that the interaction between treatment and categorical MRI subtypes did not reach the level for statistical significance in any of the MRI measures. “As hypothesized, assessing MRI subtypes through continuous severity and typicality dimensions was more sensitive to differences in response to donepezil compared with conventional categorical subtyping approach,” highlighted the researchers.

As previously found in the same cohort, there was a nonsignificant effect of donepezil treatment on cognitive measures along the MRI subtyping dimensions and across the MRI categorical subtypes. [Alzheimers Dement 2015;11:1041-1049] “Cognitive tests might be less sensitive than biological data in detecting significant changes in brain functioning at early stages of MCI,” proposed the researchers. “Furthermore, at MCI stage, cognitive decline is mild and normally progresses slowly over time. Therefore, we hypothesize that our cognitive tests have not captured these slow and mild changes and thus any potential effects of treatment over the 12-month study period.”