White Matter Disease is Associated with Widespread Grey Matter Atrophy in APOE4 non‐carriers with Early‐Stage Dementia

Abstract

AbstractBackgroundThe APOE‐ε4 (APOE4) allele and cerebrovascular disease (CVD), represented by surrogate MRI measures involving white matter hyperintensities (WMH) are key dementia risk factors [Tosto et al.,2015; Mahley et al.,2006]. They relate to grey matter volume (GMV) and cognitive decline, and demonstrate increased occurrence with lowered age of dementia onset [Boyle et al.,2016; Brickman et al.,2014]. Whether APOE4 is a key effect modifier in the relationship between WMH and GMV needs further exploration. Therefore, we examined independent and interactive effects of WMH and APOE4 on GMV and cognition in cognitively unimpaired (CU) and early‐stage dementia (ESD) participants. We hypothesized that participants with higher WMH load would demonstrate worse GMV atrophy and greater cognitive impairment, especially among APOE4 carriers.MethodWe studied 259 CU and 192 ESD (mild cognitive impairment, mild dementia) from a Singapore research cohort with neuroimaging, APOE genotyping and neuropsychological assessment data (Table 1). We investigated independent and interactive effects of WMH and APOE4 on whole‐brain voxel‐wise GMV using voxel‐based morphometry (uncorrected p<0.001; minimum cluster size=100 voxels). Multiple linear regression models assessed APOE4 and WMH interactive effects on global cognition (mini‐mental state examination–MMSE), memory (Alzheimer’s disease assessment scale‐delayed word recall) and executive function (Color Trails 2) in ESD.ResultHigher WMH load associated with widespread voxel‐wise grey matter atrophy across frontal, parietal, temporal and occipital lobes in CU and ESD (Fig.1). When stratified by APOE4 status, APOE4 carriers showed regions of GM atrophy in frontal, temporal and parietal regions. When examining the interaction between WMH and APOE4 on GMV, contrary to our hypothesis, APOE4 non‐carriers showed more extensive derogatory effects of WMH on GMV than APOE4 carriers (Fig.2). These effects extended into ESD cognitive performance with APOE4 non‐carriers displaying deteriorating global and executive function with increasing WMH load than APOE4 carriers (Fig.3).ConclusionWe illustrate APOE4 status as likely a key moderator in the relationship between WMH and GMV in both preclinical CU and ESD stages. With differential effects of WMH on GMV and cognition between APOE4 carriers and non‐carriers, interventions targeting WMH may need a differential approach depending on the APOE4 status.