White matter hyperintensities in cholinergic pathways may predict poorer responsiveness to acetylcholinesterase inhibitor treatment for Alzheimer disease

Background: Acetylcholinesterase inhibitor (AChEI) drug regimens are the mainstay treatment options for patients with Alzheimer disease (AD). Herein, we predicted clinical responses to AChEI treatment from baseline neuroimaging parameters. Methods: Between 2020 and 2021, we recruited 101 individuals with a clinical diagnosis of probable AD. Each participant underwent complete neuropsychological testing and 3T brain magnetic resonance imaging (MRI). Responsiveness to donepezil, as assessed after 12 months, was designated as less than two points of regression in Mini-Mental State Examination scores. We also evaluated MRI images by examining scores on the Cholinergic Pathways Hyperintensities Scale (CHIPS), Fazekas scale, and medial temporal atrophy (MTA) scale. Results: In our cohort, 52 patients (51.4%) were classified as responders. We observed significantly higher CHIPS scores in the nonresponder group (21.1 ± 12.9 vs. 14.9 ± 9.2, P = 0.007). Age at baseline, education level, sex, Clinical Dementia Rating sum of boxes scores, and three neuroimaging parameters were tested in regression models. Only CHIPS scores predicted clinical response to AChEI treatment. Conclusion: WMHs in the cholinergic pathways, not diffuse white matter lesions or hippocampal atrophy, correlated with poorer responsiveness to AChEI treatment. Therefore, further investigation into the role of the cholinergic pathway in AD is warranted.