APOE4 and confluent WMH have a synergistic effect on episodic memory impairment in prodromal dementia

Abstract Background White matter hyperintensities (WMH) are a known risk factor for cognitive decline (C.Puzo el. al. 2019). While the ε4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline in concomitance with WMH (D.Tsuang et. al. 2013), it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. Our objective was thus to determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. Method 216 participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain‐specific), cardiovascular risk factor assessments and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain‐specific cognitive measures (executive function, episodic memory, attention, language) in moderation analysis (Figure 1). The role of confluent and non‐confluent WMH subtype on cognition was additionally studied using moderation analysis and logistic regression (Figure 1). Result APOE4 carriers (n = 49) had poorer memory and higher global WMH (p = 0.04), temporal WMH (p = 0.01) and occipital WMH (p = 0.02) compared to APOE4 non‐carriers (n = 167). APOE4 strengthened the relationship between higher total WMH burden and worse episodic memory performance (Fig.2a). At the lobar WMH level, APOE4 strengthened associations between frontal, temporal, parietal and occipital WMH and episodic memory performance (Fig.2b, Fig.2c, Fig.2d, and Fig.2e) with large sized effects (β). APOE4 did not interact with either total or lobar WMH to predict worse cognition in other cognitive domains. Moreover, APOE4 strengthened the relationship between frontal WMH with episodic memory in the confluent WMH subgroup (Fig.2f). Logistic regression model showed memory impairment was 4.81 times more likely to develop in patients carrying APOE4 and with confluent WMH compared to APOE4 non‐carriers and those with non‐confluent WMH (OR 4.81, β 1.57, p<0.01). Conclusion The impact of WMH on memory may be strongest in APOE4 carriers at the prodromal dementia stage. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.