White matter hyperintensities in cholinergic pathways are associated with dementia severity in e4 carriers but not in non-carriers

Abstract

Background and objectives: Among individuals with Alzheimer's disease (AD), APOE 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 APOE status modulates the associations between dementia severity and white matter hyperintensities in cholinergic pathways.

Methods: From 2018 to 2022, we recruited participants (APOE e4 carriers, n = 49; non-carriers, n = 117) from the memory clinic of Cardinal Tien Hospital, Taipei, Taiwan. Participants underwent brain MRI, neuropsychological testing, and APOE 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 APOE 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 APOE 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 APOE 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 APOE e4 carriers vs. non-carriers.

Keywords: Alzheimer's disease; Cholinergic Pathways Hyperintensities Scale (CHIPS); apolipoprotein E (APOE); mild cognitive impairment; white matter hyperintensities (WMHs).

Figure 1

Illustration of CHIPS scoring on brain MRI. (A) Low external capsule, (B) high external capsule and anterior cingulate gyrus, (C) corona radiata and posterior cingulate gyrus, (D) centrum semiovale, (E) coronal view [immunohistochemical tracings of the cholinergic pathways with levels for selected slices (A–D) presented in the axial plane; drawing from Selden (31)].

Figure 2

The correlations between CDR-SB and MTA as well as CDR-SB and CHIPS in all participants. (Left) Scatterplot depicting CDR-SB scores and MTA with a simple linear regression line and 95% confidence interval (standardized beta coefficient = 0.322, R² = 0.104, adjusted R² = 0.098, p-value < 0.001). (Right) Scatterplot depicting CDR-SB scores and CHIPS scores with a simple linear regression line and 95% confidence interval (standardized beta coefficient = 0.066, R² = 0.004, adjusted R² = −0.002, p-value = 0.397). CDR-SB, clinical dementia rating scale-sum of boxes scores; MTA, medial temporal atrophy; CHIPS, Cholinergic Pathways Hyperintensities Scale.

Figure 3

The correlations between CDR-SB and CHIPS in APOE4 carriers vs. non-carriers. (Left) In carriers, scatterplot depicting CDR-SB scores and CHIPS scores with a simple linear regression line and 95% confidence interval (standardized beta coefficient = 0.319, R² = 0.101, adjusted R² = 0.082, p-value = 0.026). (Right) In non-carriers, scatterplot depicting CDR-SB scores and CHIPS with simple linear regression line and 95% confidence interval (standardized beta coefficient = −0.062, R² = 0.004, adjusted R² = −0.005, p-value = 0.509). CDR-SB, clinical dementia rating scale-sum of boxes scores; CHIPS, Cholinergic Pathways Hyperintensities Scale; Carriers, APOE e4 heterozygous or homozygous carriers; Non-carriers, APOE e4 non-carriers.