Amyloid Burden and White Matter Hyperintensities Mediate Age-Related Cognitive Differences

Abstract This study examined the additive vs synergistic contribution of beta-amyloid (Aβ) and white matter hyperintensities (WMH) across seven cognitive domains in 104 cognitively normal older adults. It also measured the extent to which age-related differences in cognition are driven by measurable brain pathology. All participants underwent neuropsychological assessment along with MRI and PiB-PET imaging for Aβ quantification. WMH severity was quantified using the ARWMC scale. Stepwise regressions, moderation and mediation modelling were performed. Our findings show that Aβ deposition single-handedly predicts poorer episodic memory performance, and that Aβ and WMH contribute additively to poorer performance in working memory and language while carrying synergistic associations with executive functions and attention. Through mediation modelling, we demonstrated that the influence of age over episodic memory, working memory, executive functions and language is fully mediated by brain pathology. This study permits to conclude that, in healthy older adults; 1) Aβ burden and WMH have synergistic associations with some cognitive domains and; 2) age-related differences in most cognitive domains are driven by brain pathology associated with dementia.