White Matter Hyperintensities in Cholinergic Pathways Are Associated with Dementia Severity in E4 Carriers but Not in Non-carriers

Background And Objectives: Among individuals with Alzheimer's disease (AD), e4 carriers with increased white matter hyperintensities (WMHs) may selectively be at increased risk of cognitive impairment. Given that the cholinergic system plays a crucial role in cognitive impairment, this study aimed to identify how status modulates the associations between dementia severity and white matter hyperintensities in cholinergic pathways.

Methods: From 2018 to 2022, we recruited participants ( e4 carriers, = 49; non-carriers, = 117) from the memory clinic of Cardinal Tien Hospital, Taipei, Taiwan. Participants underwent brain MRI, neuropsychological testing, and genotyping. In this study, we applied the visual rating scale of the Cholinergic Pathways Hyperintensities Scale (CHIPS) to evaluate WMHs in cholinergic pathways compared with the Fazekas scale. Multiple regression was used to assess the influence of CHIPS score and carrier status on dementia severity based on Clinical Dementia Rating-Sum of Boxes (CDR-SB).

Results: After adjusting for age, education and sex, higher CHIPS scores tended to be associated with higher CDR-SB in e4 carriers but not in the non-carrier group.

Conclusions: Carriers and non-carriers present distinct associations between dementia severity and WMHs in cholinergic pathways. In e4 carriers, increased white matter in cholinergic pathways are associated with greater dementia severity. In non-carriers, WMHs exhibit less predictive roles for clinical dementia severity. WMHs on the cholinergic pathway may have a different impact on e4 carriers vs. non-carriers.