We explore the relationship between white matter hyperintensity(WMH) on cholinergic pathways and the severity of cognitive impairment, with a focus on differences across APOE4 carriers and non-carriers.

Currently, no evidence has demonstrated the association between WMH and the degree of cognitive impairment. Here we apply a new visual rating scale to evaluate WMH on cholinergic pathways and hypothesize that more lesions on cholinergic pathways are associated with greater dementia severity.

From 2018 to 2021, we recruited subjects from the Memory Clinic of Cardinal Tien Hospital in Taiwan. Subjects underwent MRI, neuropsychological testing, and APOE genotyping. This study evaluated WMH within cholinergic pathway using a visual rating scale–Cholinergic Pathways HyperIntensity Scale(CHIPS), besides Fazekas scale and medial temporal lobe atrophy(MTA) score. The severity of dementia was evaluated by MMSE and Clinical Dementia Rating–Sum of Boxes(CDR-SB). The correlations and statistical interactions between CHIPS, MTA, Fazekas scale, and dementia severity were examined across e4 carriers and non-carriers.

There were 136 subjects (37 carriers, 99 non-carriers; 53 male, 83 female). The average CHIPS scores are 14.9±12.3(carriers) versus 15.0±13.3(non-carriers), p=0.8. CDR-SB in average are 3.2±3.8 versus 2.1±2.7, p=0.04. There is no correlation between Fazekas scale and dementia severity in either group. Yet it is significant that CHIPS positively correlates with CDR-SB only in carrier group(r=0.36, p=0.02); similar correlation is not found in non-carrier group(r=-0.005, p=0.59). In contrast, MTA demonstrates positive correlation in non-carriers(r=0.36, p <0.01) and does not statistically correlate with CDR-SB in the carrier group(r=0.28, p=0.1). Statistically, there is e4 interactive effect on CHIPS and CDR-SB(p<0.01).

Despite having similar CHIPS values, carriers and non-carriers present distinct correlations between CHIPS and dementia severity. WMH on cholinergic pathways positively correlates with CDR-SB only in carriers, whereas MTA only correlates with CDR-SB in non-carriers. There may be distinct pathoetiology of developing cognitive decline in e4 carriers from non-carriers.